Minimal Residual Disease

Status of minimal residual disease determines outcome of autologous hematopoietic SCT in adult ALL

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The role of autologous hematopoietic SCT (autoHSCT) in the treatment of high-risk (HR) adult ALL is controversial. In this study, we retrospectively analyzed the results of autoHSCT according to the status of minimal residual disease (MRD) at transplantation, as a joint analysis of the European Study Group for Adult ALL (EWALL). Data on 123 recipients of autoHSCT, aged 31 (16–59) years, with B-lineage (n=77) or T-lineage (n=46) ALL were included. In a cohort of Ph-negative ALL, the probability of leukemia-free survival at 5 years was higher for patients with MRD <0.1% compared with those with MRD 0.1% (57 vs 17%, P=0.0002). The difference was significant for T-lineage ALL (62 vs 8%, P=0.001), and a tendency was observed for B-lineage ALL (54 vs 26%, P=0.17). In a multivariate analysis, adjusted for other potential prognostic factors, high MRD level remained the only independent factor associated with increased risk of failure (risk ratio, 2.8; P=0.0005). We conclude that MRD determines the outcome of autoHSCT in HR adult ALL. Our results suggest the need to reevaluate the role of this treatment option in prospective trials.


First-line therapy of adults with ALL consists of remission induction followed by intensive consolidation.1 Further treatment usually depends on the presence of risk factors including initial tumor burden, age, immunophenotype, karyotype and time to achieve CR.1, 2 For patients allocated to the high-risk (HR) group, the treatment options include either allogeneic hematopoietic SCT (alloHSCT), autologous hematopoietic SCT (autoHSCT) or chemotherapy. No clear recommendations are given for patients lacking an HLA-identical sibling, and the role of autoHSCT appears to be particularly controversial.3, 4 In a number of intention-to-treat analyses, no significant differences could be shown for autotransplantation compared with conventional-dose chemotherapy.5, 6, 7 Furthermore, as shown by the MRC UKALL XII/ECOG E2993 study, administration of a single autoHSCT instead of consolidation treatment resulted in decreased leukemia-free survival (LFS).8 On the other hand, a joint follow-up analysis of 349 patients prospectively randomized in three consecutive trials conducted by the French group revealed that autoHSCT was associated with lower relapse rate compared with the chemotherapy arm and that in a cohort of 300 rapid responders who reached CR after the first induction course, this effect translated into improved LFS.9 Therefore, it seems that there may be a subgroup of patients who benefit from autoHSCT and that among factors allowing identification of this subgroup, the status of minimal residual disease (MRD), reflecting susceptibility to preceding chemotherapy, could potentially be useful. The goal of this study was to retrospectively analyze the results of autoHSCT performed in HR adult ALL patients in CR1, according to the MRD status at the time of transplantation.

Materials and methods

Study design

The data were collected on the basis of the registries of four national study groups (Polish Adult Leukemia Group, PALG; German Multicenter ALL Working Group, GMALL; Group for Research in Adult ALL, GRAALL, France; Program for Study and Treatment of Malignant Hemopathies, PETHEMA, Spain) and two individual centers (University of Brno, Czech Republic; University of Bologna, Italy), cooperating within the Study Group for Adult ALL (EWALL) of the European Leukemia Net. Inclusion criteria were as follows: (1) diagnosis of ALL, (2) age 16–60 years, (3) HR defined as the presence of at least one of the following factors: age 35 years, WBC at diagnosis 30 × 109/l for B-lineage ALL, adverse immunophenotype, that is, pro-B, early-T or mature-T, CR achieved after two induction cycles, adverse karyotype, that is, the presence of t(9;22) or t(4;11), (4) autoHSCT performed in CR1 between 1995 and 2006 and (5) MRD evaluated before autoHSCT allowing the discrimination of leukemic cells at the level of 0.1% or lower. All registered patients who met the above criteria entered the analysis.

Patients and autoHSCT procedure

One hundred-twenty-three patients with HR B-lineage (n=77) or T-lineage ALL (n=46), aged 31 years (range, 16–59 years), were evaluated. Ph-positive ALL was diagnosed in 20 (16%) cases. Median CR duration preceding autoHSCT equaled 6.3 months (range, 1.5–22.2 months). In 18 cases (14.6%), this interval was between 9 and 12 months, whereas in 5 cases (4.1%) it was longer than 12 months. All patients received at least one course of consolidation. The chemotherapy regimens varied according to the study groups. The PALG patients (n=63) were treated within the PALG 4–9610 or PALG 4–200211 study, which altogether included 196 patients, or outside prospective trials but using the same treatment protocols. GMALL patients (n=23) were included in either the GMALL 6/99 study,12 which recruited 917 subjects, or the ongoing 07/2003 protocol. In the University of Brno, the BFM protocol13 was used out of a prospective trial. GRAALL patients (n=10) were treated mostly within the GRAAPH-2003 study14 focused solely on Ph+ ALL (total recruitment n=45). In the PETHEMA (n=5), all patients were treated within the PETHEMA ALL-93 study,15 which in total included 222 subjects. Only patients with Ph+ ALL were routinely monitored for MRD and included in this analysis. In the University of Bologna, three patients with Ph+ ALL, treated according to the GIMEMA 0496 protocol,16 fulfilled the inclusion criteria for this analysis. In all protocols, autoHSCT was offered to patients lacking a suitable donor, either related or unrelated. The use of autotransplantation did not depend on MRD status, except for the GRAAPH-2003 study, in which only patients with low MRD level, defined as BCR-ABL/ABL ratio <10−4, were referred for autoHSCT. The recruitment period was 1994–2007.

The conditioning regimen was based on either TBI or chemotherapy alone. BM was used as a source of stem cells in 56 (46%) patients, peripheral blood in 66 (54%) patients, whereas both sources were applied in one case. BM was used in the majority of the PALG patients (81%), and occasionally in the University of Brno (5%) and the GMALL (4%). The graft was unmanipulated in all but one case, in which the positive selection of CD34+ cells was performed. Fifteen out of 103 Ph-negative patients received post transplant maintenance consisting of mercaptopurine and MTX for 2 years, whereas 7 out of 20 patients with Ph-positive ALL were treated with imatinib for 1 year after autoHSCT. The treatment protocols have been approved by the institutional review boards in particular study groups or centers.

Detailed patient and procedure characteristics are listed in Table 1.

Table 1 Patient characteristics and details of the autoHSCT procedure

MRD evaluation

Minimal residual disease was evaluated in BM with the use of either multiparametric flow cytometry (n=79) or molecular genetics (n=44). Flow cytometry was applied by the PALG and the University of Brno. Details of the methods changed over time; however, for most of the patients, the MRD assessment was performed with triple staining according to the recommendations of the ‘BIOMED-1 concerted action reports.’17, 18 MRD monitoring was based on the identification of cells with aberrant phenotypic features identical to leukemic cells at diagnosis. At least two different aberrant phenotypes with expression on >50% of leukemic blasts at diagnosis were used. The three main groups of analyzed aberrant phenotypes were (1) coexpression of Ags from different cell lines; (2) asynchronous Ag expression/overexpression within the same line and (3) ectopic phenotypes. The search for aberrant phenotypes from groups (1) and (3) was based on the routine ‘quadrant’ method. For group (2), the ‘empty spaces’ technique was applied as previously described.19, 20 MRD was calculated as the proportion of total nucleated BM cells. Panels of MoAbs were used as previously described.11 For PALG patients, MRD was evaluated in three laboratories. The procedure and quality of assessment was under the control of the ‘PALG Immunophenotyping Working Package.’ Results were centrally verified by the laboratory of the Department of Haematology and Bone Marrow Transplantation in Katowice.

The MRD of patients treated within the GMALL protocols was monitored on the basis of PCR amplification of Ig and TCR gene rearrangements, as previously described.12 Briefly, samples obtained at the time of diagnosis were screened for clonal Ig and TCR gene rearrangements of the IgH, Igκ-Kde, TCRβ, γ- and δ-locus. Clonal immune gene rearrangements were identified by GeneScanning and/or heteroduplex gel analysis and sequenced. MRD was then determined in cryopreserved cells from BM samples by quantitative real-time PCR using clone-specific primers for the leukemia-specific Ig/TCR gene rearrangements and a set of different germline TaqMan probes and germline primers. MRD levels were stated as the proportion of leukemic cells in normal cells, using BM mononuclear cells as a source. MRD assessment was performed in a single central laboratory.

For Ph+ ALL, quatitative evaluation of the BCR–ABL fusion gene was applied, using real-time PCR, according to published recommendations.21

As the sensitivity varied among methods, for the purpose of this study we chose the MRD level of 0.1% as a cutoff point. According to this criterion, in 76% of patients the MRD level before autoHSCT was assessed as <0.1% (low MRD group), whereas in the remaining subjects, leukemic blasts constituted 0.1% of BM cells (high MRD group) (Table 1). The exact MRD values ranged from 0 to 2%.

In most cases, the MRD status was determined directly before the start of the conditioning regimen with a median interval from MRD assessment to autoHSCT of 8 days (range, 4–87 days). The interval from the last chemotherapy course preceding autoHSCT to MRD evaluation was 26 days (range, 21–138).

Statistical methods

The probability of LFS at 5 years was the primary study end point. LFS was defined as the time interval from autoHSCT to either hematologic relapse or death in CR, and was estimated using the Kaplan–Meier method.22 Log-rank test was used to evaluate the univariate effect of MRD status on LFS, whereas the Cox proportional hazards model was applied to adjust the results for other potential prognostic factors.23 Owing to differences regarding patient selection, therapy regimens, and methodology of MRD evaluation, individuals with Ph+ ALL were excluded from uni- and multivariate analyses.


With the median follow-up of 3.8 years (range, 0.3–9.8 years), the probability of LFS for the whole group at 5 years equaled 48% (s.e., ±5%). Three out of 123 patients (2.4%) died of transplantation-related complications, whereas in the remaining subjects, relapse was the reason for failure. The probabilities of LFS were comparable for patients treated in the major contributing study groups, that is, PALG (44±7%), GMALL (39±11%) and Brno (43±15%) (P=0.56).

In the cohort of Ph ALL, the LFS rate at 5 years was higher for patients with low MRD level compared with those with high MRD status at transplantation (57±6 vs 17±8%, P=0.0002) (Figure 1). A subgroup analysis revealed a significant difference for T-lineage ALL (62±9 vs 8±7%, P=0.0001) and a tendency for B-lineage disease (54±8 vs 26±13%, P=0.17). With regard to the source of stem cells, the impact of MRD status could be shown for peripheral blood transplantations (70±8 vs 10±9%, P<0.0001) but not for BMTs (47±8 vs 24±13%, P=0.3) (Figure 2). The impact of MRD status on LFS was observed in patients in whom MRD was evaluated using flow cytometry (58±6 vs 17±9%, P=0.003), as well as in those monitored with PCR for Ig/TCR gene rearrangements (49±14 vs 14±13%, P=0.02). Evaluation of this effect in a subgroup of patients monitored for the BCR–ABL fusion gene was impossible because of the insufficient number of subjects.

Figure 1

Leukemia-free survival after autologous hematopoietic SCT high-risk Ph-negative adult ALL patients in CR1, according to minimal residual disease (MRD) status at transplantation.

Figure 2

Effect of minimal residual disease (MRD) on results of autologous hematopoietic SCT in subgroups defined by immunophenotype and source of stem cells. AutoPBSCT=autologous PBSCT; autoBMT=autologous BMT.

In a univariate analysis, the MRD status at transplantation was the only factor affecting outcome (Table 2a). Also, in a multivariate model adjusted for CR duration, age, immunophenotype, type of conditioning, source of stem cells for transplantation, and the use of post transplant maintenance, the MRD level 0.1% remained the only independent prognostic factor associated with increased risk of failure (risk ratio, 2.8; 95% confidence interval, 1.6–5, P=0.0005) (Table 2b).

Table 2 Factors affecting outcome after autoHSCT for high-risk adult Ph-negative ALL patients in CR1

In the analysis of a selected group of 50 patients in whom the MRD was evaluated with sufficient sensitivity to define the MRD status as negative at the level of 0.01%, the 5-year probability of LFS was 69% (±7%). In this cohort, three patients died of transplant-related complications (infections n=2, secondary myelodysplastic syndrome n=1), whereas 13 patients relapsed. In a subgroup of 15 BCR–ABL-positive patients with MRD <0.01%, the LFS rate at 3 years equaled 73% (±11%). Among BCR–ABL-positive ALL, the 3-year LFS rate equaled 64 (±13%) if no maintenance was administered compared with 67% (±13%) for patients treated with post transplant imatinib (P=0.75).


For HR ALL patients who completed consolidation therapy, alloHSCT from an HLA-identical relative is a recommended option.3 This was shown by the LALA-94 study showing advantage for patients having over those lacking a sibling donor.5 However, similar studies by other investigators did not reveal significant differences, which could be explained by the high incidence of non-relapse mortality following alloHSCT.6, 7, 8 As an HLA-identical sibling cannot be identified in a majority of adults, transplantation from a matched unrelated volunteer has been proposed as an alternative option. A retrospective comparison by Kiehl et al.24 revealed no differences in outcome between related and unrelated transplantations, but the non-relapse mortality rate exceeded 40% regardless of the donor type.

AutoHSCT offers a chance to administer myeloablative treatment with low risk of non-relapse mortality. On the other hand, as no GVL reaction is present after autoHSCT and there is a risk of graft contamination and re-transplantation of leukemic cells, relapses are the major reason for failure. The randomized studies published so far did not show significant advantage of autoHSCT either in comparison with alloHSCT or conventional-dose chemotherapy.4, 5, 6, 7 This led to a general tendency to avoid autotransplantation in HR ALL.4

Taking into account that the efficacy of autoHSCT relies mainly on the chemosensitivity of the disease as well as on the tumor burden, we hypothesized that the level of MRD, reflecting both the above features, may determine the outcome of the autotransplantation. As in our study group various techniques, characterized by various sensitivity levels, were used for MRD assessment, we chose 0.1% of BM cells as the most convenient cutoff point. We were able to show for the first time that the MRD level influences outcome after autoHSCT in adults with HR Ph-negative ALL. The results of both univariate and multivariate analysis indicated that the MRD status is the most important determinant of LFS. It must be stressed, however, that our results should be interpreted with caution as the study was retrospective and the analyzed group was heterogeneous with regard to the methodology of MRD assessment, chemotherapy protocols and the transplantation procedure. Indeed, various techniques to determine MRD could not necessarily correlate. As recently shown, the analysis of the BCR–ABL fusion gene may be more adequate to predict relapse compared with the analysis of the Ig/TCR gene rearrangement.25 For this reason, as well as considering that only three BCR–ABL-positive patients had MRD >0.1% at the time of autoHSCT, we have decided to exclude Ph+ ALL from uni- and multivariate analyses. However, for Ph ALL there may also be differences between the MRD levels obtained with PCR-based methods and flow cytometry.26 For example, in our study group, in case of Ig/TCR gene rearrangement, MRD was reported in the context of BM mononuclear cells, whereas for flow cytometry, all nucleated cells were considered. To diminish the risk of misinterpretation, we performed additional analyses showing a significant impact of MRD status on outcome separately for patients monitored with flow cytometry and Ig/TCR gene rearrangement.

The efficacy of autoHSCT may be affected by the preceding conventional-dose chemotherapy protocols and transplantation procedure. In our study group, patients were treated according to eight different chemotherapy protocols. In addition, BM was used mainly by the PALG, whereas all other groups preferentially used peripheral blood as a source of stem cells. Once again, we performed subgroup analyses showing that the results for the three major cohorts, that is, PALG, GMALL and Brno, were comparable. In addition, the effect of MRD status on LFS in the above subgroups remained significant (P=0.04, 0.02, 0.047, respectively; data not shown).

In our analysis, the prognostic value of MRD assessed before autoHSCT could be statistically proven for T-lineage ALL, whereas only a tendency was observed for B-precursor disease. Similarly, the effect was significant for transplantations performed using peripheral blood as a source of stem cells, but not for BMTs. Additional analysis combining disease subtypes and sources of stem cells indicated a significant effect of MRD on LFS only in T-ALL patients treated with peripheral blood transplantations (P=0.001, data not shown). The above findings could be a consequence of the limited number of subjects included in the subgroup analyses. On the other hand, it cannot be excluded that the biology of T-cell and B-cell ALL differs and that the different cutoff point for MRD should be applied, depending on the disease subtype.27 In addition, it has been shown that in the case of BCR–ABL-positive ALL, BMTs contain more residual leukemic cells compared with peripheral blood cells.28 Unfortunately, we did not have data on the transplant material contamination among the analyzed patients, but it may be speculated that the MRD threshold of 0.1% may be too high to detect differences with regard to BMT, whereas it is sufficient in case of peripheral blood.

Direct comparison of our results with other reported series is difficult because of the retrospective nature of the analysis as well as scarce data in the literature available for HR adult ALL according to the MRD status. In our cohort, the median interval from CR to autoHSCT equaled 6.3 months, and was similar for patients with low and high MRD levels (6.4 vs 6.1 months, P=0.87). According to modern treatment protocols, this interval used to be necessary to complete consolidation. In a recently reported series by the Polish Adult Leukemia Group, the 3-year LFS rate for HR patients with MRD <0.1% after consolidation equaled 35%, despite the use of alloHSCT in 40% of subjects.11 These results seem to be markedly inferior compared with our results obtained for autoHSCT in patients with low MRD level. Particularly high probabilities of LFS could be shown for patients with MRD <0.01%, including very HR patients as defined by the presence of BCR–ABL. It appears that autoHSCT in BCR–ABL-positive ALL with very low MRD levels may allow long-term disease control even without post transplant imatinib maintenance, which however should be interpreted with caution as the number of subjects was rather small. Furthermore, other conventional risk factors including age and initial WBC do not seem to predict outcome after autoHSCT. It should be stressed, however, that patients referred for transplantation procedure are by definition a pre-selected population as many potential candidates relapse in earlier course of the disease. Therefore, the effect of risk factors other than MRD status may not persist at the time of autoHSCT.

Although the results of our study do not provide direct evidence for the efficacy of autoHSCT, they suggest that this option may still be of value for HR adults with ALL. It may be hypothesized that patients with low tumor burden, defined on the basis of MRD, particularly benefit from high-dose therapy followed by autoHSCT, which, however, requires verification in prospective trials.

We conclude that MRD status is the most important predictor of outcome in HR adult ALL patients treated with autoHSCT in CR1. Our results suggest the need for further prospective trials, as it may contribute to a reevaluation of the role of autoHSCT in the treatment of adults with ALL. The prospective studies could be focused on the comparison of autoHSCT and standard-dose chemotherapy in a selected group of patients with low MRD level lacking appropriate donor. Keeping in mind the results of the MRC UKALL XII/ECOG E2993 study,8 the transplantation should rather be performed after the completion of consolidation chemotherapy as an alternative to maintenance.


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The contributions of the scientists involved in MRD assessment, Krystyna Jagoda, PhD, Agnieszka Balana-Nowak, PhD, Monika Brüggemann PhD, and Thorsten Raff, PhD, are acknowledged.

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Correspondence to S Giebel.

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  • auto transplant
  • ALL
  • minimal residual disease

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