Relapse of Ph chromosome-positive ALL (Ph+ALL) results from the persistence of leukemia-propagating cells (LPCs). In Ph+ALL, a xenograft assay recently determined that LPCs are enriched in the CD34+CD38−CD58− fraction. Therefore, the prognostic significance of LPCs in Ph+ALL subjects after allogeneic hematopoietic SCT (allo-HSCT) was investigated. A total of 80 consecutive adults with Ph+ALL who underwent allo-HSCT were eligible. A multi-parameter flow cytometry analysis examining CD58–FITC/CD10–PE/ CD19–APC–Cy7/CD34–PerCP/CD45–Vioblue/ CD38–APC on gated leukemia BM blasts was performed at diagnosis. Based on the original blast phenotypes, subjects were stratified into the CD34+CD38−CD58−group (N=15) and other phenotype group (N=65). During minimal residual disease monitoring, significantly higher levels of BCR/ABL transcripts were detected in subjects in the CD34+CD38−CD58− group than in other phenotype group, especially at 3 months post HSCT. In addition, CD34+CD38−CD58−LPCs are directly correlated with a higher 3-year cumulative incidence of relapse (CIR) and worse leukemia-free survival (LFS) and OS. Multivariate analyses indicated that presence of CD34+CD38−CD58− LPCs at diagnosis, and BCR–ABL reduction at 3 months post HSCT were independent risk factors for relapse, LFS and OS. Our data suggest that presence of CD34+CD38−CD58− LPCs at diagnosis allows rapid identification of high-risk patients for relapse after allo-HSCT.
The Ph chromosome, resulting from a reciprocal translocation between chromosomes 9 and 22 and leading to the generation of the BCR–ABL fusion gene, encodes a constitutively active protein tyrosine kinase and is present in 20–30% of adult patients with ALL.1, 2 Despite the widespread use of Abelson tyrosine kinase inhibitors to treat Ph-positive ALL (Ph+ALL), allo-hematopoietic SCT (allo-HSCT) is currently considered the best curative option. Administration of tyrosine kinase inhibitors pre and post transplantation has further improved the prognosis of Ph+ALL. Nevertheless, relapse is still the main cause of treatment failure even after allo-HSCT.1, 3, 4, 5 Once patients experience a relapse, the outcomes are extremely unfavorable. Therefore, it is imperative to identify novel prognostic factors to predict relapse in Ph+ALL after allo-HSCT.
Leukemia-propagating cells (LPCs) are defined by their ability to initiate human leukemia and to proliferate and self-renew in immune-deficient mice.6, 7, 8 Higher LPC frequencies and a gene expression profile typical of LPCs at diagnosis are predictive of unfavorable clinical outcomes in AML.9, 10, 11, 12 Recently, we reported that LPCs in Ph+ALL are enriched in the CD34+CD38−CD58− fraction using an anti-CD122-conditioned NOD/SCID xenograft assay by intra-BM injection. Moreover, our preliminary data indicate that a CD34+CD38−CD58− LPC phenotype at diagnosis is an independent risk factor for relapse in a cohort of 63 patients with de novo Ph+ALL.13 However, it is unclear if the reliability of the LPC phenotype to identify patients at high risk for relapse is relevant to Ph+ALL patients after allo-HSCT. Consequently, we conducted a cohort study to investigate the impact of the CD34+CD38−CD58− LPC phenotype at diagnosis on allo-HSCT outcomes in 80 adults with Ph+ALL.
Materials and methods
Eighty consecutive adults with Ph+ALL who received allo-HSCT at Peking University Institute of Hematology from 1 January 2009 to 31 December 2013 were eligible for this study. The inclusion criteria were as follows: (1) patients were 18–60 years old; (2) diagnosis of Ph+ALL was based on the 2008 WHO (World Health Organization) criteria; (3) allo-HSCT from any source (either HLA-matched sibling donor, HLA-matched unrelated donor or HLA-mismatched/haploidentical donors) was acceptable; and (4) no contraindications to imatinib or an allotransplant. Patients were excluded if either hematological relapse or extramedullary leukemia involvement was diagnosed after initial engraftment or if the life expectancy was <1 month post HSCT. Comprehensive clinical data were available for all subjects (Table 1). The study was approved by the Ethics Committee of Peking University People’s Hospital, and written informed consent was obtained from all subjects before entering the study in accordance with the Declaration of Helsinki.
Definition of the CD34+CD38−CD58−LPC phenotype
Multi-parameter flow cytometry analyses of CD58–FITC (Beckman-Coulter, Brea, CA, USA)/CD10–PE/CD19–APC–Cy7/CD34–PerCP/CD45–Vioblue/CD38–APC (BD Biosciences, San Jose, CA, USA) on gated BM leukemia blasts from subjects were performed at diagnosis using a multi-color MACSQuant Analyzer (Miltenyi Biotec, Bergisch Gladbach, Germany). Fluorescence-minus-one controls14, 15 were used to identify positive events for CD34, CD38 and CD58. Samples in which ⩾20% of the blasts expressed the relevant CD Ag were considered positive.16 Based on the blast phenotypes at diagnosis, subjects were further divided into the CD34+CD38−CD58−group and other phenotype group (including subjects with CD34+CD38−CD58+, CD34+CD38+CD58− or CD34+CD38+CD58+ phenotypes and subjects with all of the above defined four fractions) as previously described.13 Analyses were performed using MACSQuant software (Miltenyi Biotec).
All of the subjects received uniform first-line imatinib-based induction and consolidation chemotherapy as previously reported.13 After two cycles of consolidation, subjects with a suitable donor, including a matched sibling donor, haploidentical donor or HLA-matched unrelated donor, received an allo-HSCT. The transplant protocols, including donor selection, HLA typing and stem cell harvesting, pre-transplant conditioning regimens and prophylaxis of GVHD, were conducted as described previously in detail.17, 18, 19, 20 Imatinib treatment was scheduled for 3–12 months post HSCT, after the BCR–ABL transcript levels were negative for at least three consecutive tests or major molecular remission (MMR) was sustained for at least 3 months, as described in our previous report.3
Minimal residual disease (MRD) assessment
BCR/ABL transcript levels in BM samples were monitored at diagnosis; directly before transplantation; 1, 2, 3, 6, 9, 12, 24, 36 and 60 months post HSCT; and at relapse using RQ–PCR as previously described.20, 21 In patients with a >1log rising level of BCR/ABL transcripts, monitoring was performed every 2 weeks. BCR/ABL primers and probes amplifying the b3a2 and b2a2 junctions were used for detection according to recommendations of the Europe Against Cancer Program.22, 23 The results were expressed as a transcript ratio and calculated as [fusion gene/ABL] × 100.
Hematopoietic engraftment post transplantation was defined as the reconstitution of both neutrophil and plts numbers. Neutrophil reconstitution was defined as occurring after the first 3 consecutive days with an ANC >0.5 × 109/L, and plt reconstitution was defined as the first time levels reached >20 × 109/L for 7 consecutive days. Chimerism analysis was performed using DNA fingerprinting for STRs in blood samples and/or chromosome FISH of BM samples. Full donor chimerism was defined as the absence of detectable recipient hematopoietic or lymphoid cells using either of the above methods. Poor graft function (PGF, both primary and secondary) was defined as the presence of 2 or 3 cytopenic counts (ANC⩽0.5 × 109/L and PLT⩽20 × 109/L or Hb⩽70 g/L) for at least 3 consecutive days beyond 28 days post-transplantation as well as a transfusion requirement associated with hypoplastic-aplastic BM in the presence of complete donor chimerism.24 Secondary PGF was defined as recurrent pancytopenia reaching levels fulfiling the diagnostic criteria for PGF after achieving good graft function in the absence of severe GVHD or hematological relapse. Hematological relapse was determined by the reappearance of blasts in the blood, BM (>5%) or any extramedullary site after CR using common morphological criteria. GVHD was scored as acute or chronic based on published criteria.17, 18, 19, 20
MMR was defined as a ⩾3 log reduction in BCR/ABL transcripts levels compared with the individualized pretreatment baseline. Non-MMR was defined as <3 log reduction in BCR/ABL transcripts levels.
End points and statistical analyses
The primary endpoint was relapse, whereas the secondary endpoints were leukemia-free survival (LFS) and OS. Cumulative incidence of relapse (CIR) and NRM were calculated using the Kalbfleisch and Prentice method. Differences in CIR between the subgroups were assessed according to the Gray test using R software. The probabilities of LFS and OS were estimated using the Kaplan–Meier method and compared using the log-rank test. Univariate analyses were performed using the χ2-test for categorical variables and the Mann–Whitney U-test for continuous variables. Factors at a level of P<0.1 were included as variables in the multivariate Cox regression model. P<0.05 was considered significant unless otherwise specified. The SPSS 16.0 (IBM, Armonk, NY, USA), GraphPad Prism 5.0 (GraphPad Software, La Jolla, CA, USA) and R (Bell Labs, New Providence, NJ, USA) software packages were used for all data analyses. Surviving subjects were accounted for on 1 July 2014.
A total of 80 consecutive adults with Ph+ALL who underwent allo-HSCT were enrolled in this study. Imatinib therapy was administered to all of the subjects pre HSCT. Five subjects did not receive imatinib therapy post HSCT for the following reasons: pancytopenia (N=3) or severe gut GVHD (N=2). The median follow-up time was 25.5 months (range, 6–65 months) for all of the subjects and 33 months (range, 6–65 months) for survivors. A total of 77 subjects (96.25%) achieved sustained hematopoietic engraftment. Twelve (15%) subjects relapsed, and 59 (73.75%) remained in continuous CR. Twenty-one subjects died (9 from NRM and 12 from relapse), and 59 subjects survived to the median of 33 months after transplantation (range, 6–65 months). As illustrated in Figure 1, CIR at 3 years was 17.5% (95% confidence interval, 16.03–18.97%), and NRM at 3 years was 13.98% (13.59–14.37%). Three-year probabilities of LFS and OS were 68.51% (55–78.72%) and 72.34% (58.76–82.11%), respectively.
Impact of the CD34+CD38−CD58− LPC phenotype on clinical outcomes
According to previously reported gating strategies,13 the CD34+CD38−CD58− LPC phenotype was detected in 15 subjects at diagnosis, whereas 65 subjects showed the other phenotype. As summarized in Table 1, the demographic and clinical characteristics showed no significant differences between the two phenotypic groups.
Chimerism analysis indicated that all subjects (N=80) achieved full donor chimerism by 30 days post HSCT. Except for the three subjects with secondary PGF in the other phenotype cohort, the cumulative 30-day myeloid engraftment probability and 60-day platelet engraftment probability were 93.33% and 86.67%, respectively, in the CD34+CD38−CD58−cohort compared with 95.38% and 89.23% in the other phenotype cohort. Moreover, no significant differences were demonstrated in the median time to myeloid engraftment (18 days vs 13 days, P=0.83) and platelet engraftment (21 days vs 15 days, P=0.92) between the CD34+CD38−CD58−cohort and the other phenotype cohort.
As shown in Table 1, BCR/ABL transcripts in the CD34+CD38−CD58− cohort directly, pre HSCT, did not differ significantly from the transcript levels in the other phenotype cohort (0.09 (0–22.6)% vs 0.04 (0–54.2)%; P=0.56). Significantly higher levels of BCR/ABL transcripts were detected in subjects from the CD34+CD38−CD58− cohort compared with subjects in the other phenotype cohort at 2 months post HSCT (0.01 (0–50.8)% vs 0 (0–96.8)%; P=0.02) and, in particular, at 3 months post HSCT (0.12 (0–152.4)% vs 0 (0–100)%; P=0.001).
In the CD34+CD38−CD58− cohort, 8 of 15 subjects who underwent HSCT relapsed compared with 4 of 65 subjects in the other phenotype cohort (P<0.0001). Relapse occurred at a median of 13 months (3–28 months) post transplantation in the CD34+CD38−CD58− cohort and at 14.5 months (6–45 months) in the other phenotype cohort. CIR at 3 years in the CD34+CD38−CD58− cohort was significantly higher compared with CIR in the other phenotype cohort (63.2% (58.2–68.1%) vs 5.3% (5.1–5.5%); P<0.0001; Figure 2a). Other variables significantly associated with CIR in univariate analyses included MMR at 3 months post HSCT (P<0.0001) and disease status pre HSCT (P<0.0001). The LPC phenotype at diagnosis and MMR at 3 months post HSCT were independently correlated with relapse in the multivariate analyses (Table 2).
The three-year LFS of subjects in the other phenotype cohort was significantly higher than in subjects in the CD34+CD38−CD58− cohort (78.7% (64.5–87.7%) vs 30.2% (8.1–56.6%); P=0.001; Figure 2b). MMR at 3 months post HSCT (P<0.0001) and disease status pre HSCT (P<0.0001) were also significantly correlated with LFS in the univariate analyses. In multivariate analyses, the LPC phenotype at diagnosis and MMR at 3 months post HSCT were independently correlated with LFS (Table 2).
The CD34+CD38−CD58− cohort exhibited poorer 3-year OS than the other phenotype cohort (37.7% (12.6–63.2%) vs 82.3% (68.5–90.4%); P=0.0004; Figure 2c). MMR at 3 months post HSCT (P<0.0001) and disease status pre HSCT (P<0.0001) were correlated with survival in the univariate analyses. In multivariate analyses, the LPC phenotype at diagnosis and MMR at 3 months post HSCT were independently correlated with OS (Table 2).
A new risk stratification model was established by integrating the analysis of the CD34+CD38−CD58− LPC phenotype at diagnosis and MMR at 3 months post HSCT
Based on the multivariate analyses, three distinct prognostic groups (the LPC+ and non-MMR group, the other group (LPC− and non-MMR or LPC+ and MMR) and the LPC− and MMR group) were further classified by integration of the two independent risk factors, including the CD34+CD38−CD58− phenotype at diagnosis (LPC+=CD34+CD38−CD58− phenotype, LPC−=other phenotype) and MMR at 3 months post HSCT (non-MMR= BCR–ABL reduction<3 log, MMR=BCR–ABL reduction⩾3 log). These groups significantly showed different 3-year CIR values (100% vs 49.35% (41.53–51.17%) vs 5.47% (5.27–5.67%); P<0.0001; Figure 3a), LFS (0% vs 37.98% (9.71–66.91%) vs 80.20% (66–88.95%); P<0.0001; Figure 3b) and OS (0% vs 50.35% (17.04–76.64%) vs 83.86% (70.02–91.67%); P<0.0001; Figure 3c), respectively.
To our knowledge, our current cohort study is the first to demonstrate that the presence of CD34+CD38−CD58− LPCs at diagnosis is significantly correlated with a higher MRD frequency and a 3-year CIR in Ph+ALL patients after allo-HSCT. Prospective evaluation of CD34+CD38−CD58− LPCs at diagnosis might allow the identification of subgroups of Ph+ALL transplant patients at high risk for relapse.
Relapse remains one of the major obstacles to Ph+ALL treatment after allo-HSCT, with an estimated 4-year relapse of 38% in a UKALL12/E2993 study.4 In a Japanese adult leukemia study, an estimated 3-year CIR of 21% was observed in an imatinib cohort, which was significantly lower than that in the non-imatinib cohort (34%).5 Our previous study demonstrated that patients treated with imatinib maintenance therapy guided by BCR-ABL monitoring by RQ–PCR after allo-HSCT have a lower estimated 5-year relapse rate (10.2%) compared with patients not treated with imatinib (33.1%).3 However, challenges remain in implementing the experimentally validated biomarkers for recurrence prediction for risk-stratification therapy in Ph+ALL after allo-HSCT. In agreement with our previous report for de novoPh+ALL,13 the novel CD34+CD38−CD58−LPC phenotype has significant power to identify patients at high risk for relapse post HSCT. Although allo-HSCT exhibits the strongest anti-leukemia effects, it could not completely overcome the high risk of relapse in adult Ph+ALL patients with the candidate LPC phenotype. Assessment of the CD34+CD38−CD58− LPC phenotype can be easily incorporated into routine diagnostic protocols to predict recurrence and guide individualized post-transplantation therapy. We are aware, however, that this is a single cohort study enrolling 80 patients with Ph+ALL after allo-HSCT. This approach requires prospective validation in a multicenter prospective cohort study with more patients.
For Ph+ALL outcomes, other prognostic factors have been proposed, such as BCR/ABL-based MRD monitoring. Reports from the pre-tyrosine kinase inhibitor era suggested a strong correlation between BCR/ABL quantification and recurrence.25, 26 However, it remains controversial whether BCR/ABL-based MRD monitoring pre and post HSCT continues to serve as an efficient tool for risk stratification after HSCT.27, 28, 29, 30 Our study demonstrates the prognostic relevance of MRD kinetics to relapse and strongly supports a prior report from the GMALL Study Group,28 which found that patients with the appearance of BCR/ABL transcripts early (<100 days) and/or at higher levels (>10−3) after allo-HSCT show a limited benefit from imatinib treatment. Unlike a previous study by Lee et al.,27 our data indicate that MRD status pre HSCT is not significantly correlated with recurrence post HSCT. An insufficient molecular response pre HSCT suggests that although first-line imatinib-based chemotherapy is highly active against leukemic bulk, it is not effective against the LPCs responsible for relapse.31, 32 It is therefore conceivable that subsequent allo-HSCT might partially compensate for this insufficiency due to the GVL effect; therefore, MRD kinetics post HSCT might be more closely associated with the outcomes. Remarkably, a new risk stratification model is further established by the combined analyses of pre-HSCT (CD34+CD38−CD58− LPCs at diagnosis) and post-HSCT parameters (MMR at 3 months post HSCT), which is helpful to identify a small subset of patients at ‘very high risk’ of relapse (100%) post transplantation. Consequently, rapid identification of high-risk patients based on the pre-HSCT parameter(CD34+CD38−CD58− LPCs at diagnosis) might allow patients to be treated with prophylactic interventions such as new tyrosine kinase inhibitors,33, 34 DLI19, 35 or interferon alpha36, 37 early after allo-HSCT for the prevention of relapse and the improvement of transplant outcomes in adult Ph+ALL.
IKZF1-deletions were recently identified to correlate with relapse in Ph+ALL.38, 39 In the present cohort study, IKZF1-deletions were analyzed in 52.5% of the subjects, which made it difficult to directly compare the impact of the LPC phenotype or IKZF1-deletions on post-HSCT outcomes. It should be noted, however, that our preliminary results demonstrated that the frequency of IKZF1-deletions at diagnosis were comparable between the two phenotypic groups, which emphasizes the prognostic significance of the LPC phenotype. In the future, it would be of value to investigate the two risk factors in prospective randomized studies with larger patient cohorts.
In conclusion, our data suggest that the presence of CD34+CD38−CD58− LPCs at diagnosis allows rapid identification of high-risk patients of relapse after allo-HSCT. Risk-stratification post-HSCT therapy, incorporating an analysis of the CD34+CD38−CD58− LPC phenotype at diagnosis, shows promise to benefit adults with Ph+ALL in the future.
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This work was supported by the National Natural Science Foundation of China (grant no. 81370638 & 81230013), the Beijing Municipal Science and Technology Program, the National Clinical Priority Specialty and the Peking University People’s Hospital Research and Development Funds (grant no. RDB2012-23). American Journal Experts (www.journalexperts.com) offered editorial assistance to the authors during the preparation of this manuscript. We thank all of the core facilities at the Peking University Institute of Hematology for sample collection.
X-JH designed the study and supervised the analyses and manuscript preparation. YK performed the research, analyzed and interpreted the data, performed statistical analyses and wrote the manuscript. All other authors participated in the collection of patient data. All the authors agreed to submit the final manuscript.
The authors declare no conflict of interest.
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