Ph chromosome and BCR-ABL fusion gene mark the most unfavorable subgroup of ALL.1 Currently, the integration of imatinib into traditional chemotherapy-based induction therapy has been proved to increase overall rate of CR and improve long-term survival. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is recommended as the mainstay of post-remission therapy.2 In spite of these exciting improvements, a substantial number of transplant patients subsequently die on account of disease progression. Identifying early warning predictors for relapse has consequentially become of paramount importance. Relying on the breakthrough in molecular biotechniques, modern minimal residual disease (MRD) monitoring has been gradually accepted as an accurate and reliable prognostic indicator superior to conventional factors.3 Nevertheless, which timepoint displaying the strongest prognostic power in adult Ph+ ALL transplants remains inconclusive.
From July 2006 to October 2014, a total of 65 adult Ph+ ALL patients who underwent allo-HSCT in first remission were enrolled in this retrospective study, which followed approval by the Ethics Committee and the observation of Declaration of Helsinki conditions. All patients received a combined chemotherapy regimen of CDVP for induction, and a regimen comprising high-dose methotrexate (MTX) and high-dose Ara-C for consolidation.4 Imatinib at a dose of 600 mg daily was introduced as a supplement of induction in 48 patients (26 patients during the first 14 days) and at a dose of 400 mg daily in all patients as part of consolidation. Patients with an HLA-matched donor then proceeded to transplantation. The conditioning regimen and GvHD prophylaxis of our center were reported elsewhere.5 Imatinib was administered at a dose of 400 mg daily, 1 month after transplantation. Marrow examination was performed after each course of treatment regimen, before allo-HSCT and at 1, 3, 6, 12 months after transplantation. Major molecular response (MMR) was defined as BCR-ABL/ABL ratio of <0.1% or a reduction in BCR-ABL transcript level by at least 3-log from pretreated baseline.6
The data were displayed as percentages for categorical variables and medians (range) for continuous variables, respectively compared with the X2 test and Wilcoxon test to estimate significant differences. Overall survival (OS) and relapse-free survival (RFS) were assessed using the Log-rank test. Cumulative incidence of relapse (CIR) was calculated by Gray’s test. Independent prognostic risk factors were identified in a multivariate linear regression analysis using a stepwise backward elimination of significant variables. The data were updated in March 2015. SPSS 17.0 (SPSS, Chicago, IL, USA) and R version 2.15.1 (R Foundation for Statistical Computing, Vienna, Austria) software were used for statistical analyses. Two-sided P<0.05 was defined to be statistically significant.
Patient characteristics are summarized in Table 1. The median age was 29 years (range, 16–54). The median WBC count was 45 × 109/L (range,1–553). Sixty one (93.8%) patients achieved hematological CR after the first induction and all after the second. Only 16 (24.6%) patients acquired post-induction MMR. For patients treated with a combined regimen of chemotherapy plus imatinib, 15 (31.3%) acquired MMR, significantly higher than patients treated with chemotherapy alone (5.9%, P=0.021). The incorporation of imatinib during the first 14 days led to a marginal, but not significant, difference (42.3% in the early group compared with 18.2% in the late group, P=0.068).
Thirty-five (53.8%) patients were in MMR status before transplantation. Imatinib integration during induction failed to increase pre-HSCT MMR rate, as that of 26/48 (54.2%) in the imatinib-based chemotherapy group versus 9/17 (52.9%) in the chemotherapy-alone group (P=0.931).
The median follow-up was 18 (range, 3–76) months. The median time of post-transplantation relapse in 14 patients was 9 (range, 2–33) months. 8 (57.1%) relapses occurred during the first year and 4 (28.6%) during the second. There was a weak relationship between post-induction MMR and OS (Figure 1a, P=0.3412), RFS (Figure 1b, P=0.1310), and CIR (Supplementary Figure 1A, P=0.0694). Pre-HSCT MMR, however, was associated with a decreased likelihood of post-transplantation relapse, with the 2-year estimate of CIR dropping from 38.3% in the none-MMR group to 13.4% (Supplementary Figure 1B, P=0.0108). Furthermore, we found a significant difference between the rate of survival in these two cohorts of patients. Specifically, pre-HSCT MMR improved the 2-year estimate OS to 81.9%, and RFS to 70.3%, superior to 57.8% (Figure 1c, P=0.0455) and 40.2% (Figure 1d, P=0.0291) in the none-MMR group.
To better interpret the predictive value of MRD, we allocated all patients into four groups in compliance with MRD status at both timepoints, that is, both post-induction and pre-HSCT MMR (T1+2, n=14), only post-induction MMR (T1, n=2), only pre-HSCT MMR (T2, n=22) and none-MMR (n=27). Results showed that persistent undetectable leukemic residual featured the optimal outcome (Figures 1e and f, 2-year estimate of 84.4% for OS, P=0.0955 and 84.4% for RFS, P=0.0275), succeeded by only pre-HSCT MMR patients.
We also performed a Cox proportional hazard analysis to corroborate the independent predictive nature of all possible factors on the probability of outcomes. Our data highlighted a good correlation between pre-HSCT MMR with a superior outcome (OS, HR: 3.856 (1.316–11.293), P=0.014 and RFS, HR: 2.581 (1.179–5.650), P=0.018) and a decreased likelihood of relapse (CIR, 3.410 (1.048–11.102), P=0.042). Failure in achieving post-induction MMR (CIR, 8.774 (1.016~17.780), P=0.048) and additional chromosomal abnormality (CIR, 1.799 (1.058–3.060), P=0.030) were independent predictive factors for relapse.
In this study, we evaluate the impact of pre-HSCT MRD status on outcomes of Ph+ ALL transplants. Over the last decade, although several studies reported contradictory results,7 most findings have demonstrated MRD to be a powerful prognostic tool. Our data exhibited a good correlation of pre-HSCT MMR with less relapse and better survival in Ph+ ALL transplants. With this information in mind, several approaches could be attempted such as more intensive chemotherapy or second-/third-generation TKI integration to reduce the disease burden before transplantation.8 However, treatment intensification in these efforts may be detrimental due to additional organ toxicity and increasing transplantation-related deaths. This suggests to us that, prophylactic measures, including for example, post-transplantation TKIs,9 or immune-modulation that involves immune suppression withdrawal or donor lymphocyte infusion (DLI)10 could be considered to maintain or reproduce MMR, particularly for patients at high residual burden before transplantation.
In spite of the limitation that our study was performed retrospectively, as the BCR-ABL quantitative level did not affect therapy options, we were able to investigate on the informative value of MRD in Ph+ ALL transplants, and therefore to provide information justifying further incorporation of this factor into future risk classification and treatment strategies.
In summary, MRD has redefined remission in Ph+ ALL. The acquisition of MMR prior to HSCT was the strongest prognostic factor in Ph+ ALL transplants.
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We express our gratitude to all the participants for contribution to this study, and we also extend our thanks to all the patients in this study. This study was funded by National Natural Science Foundation of China (81270617), Jiangsu Province’s Key Medical Center (ZX201102) as well as Jiangsu Province’s Key Medical Center (ZX201102).
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on Bone Marrow Transplantation website
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Cai, WZ., Cen, JN., Chen, J. et al. Major molecular response prior to allogeneic hematopoietic stem cell transplantation predicts better outcome in adult Philadelphia-positive acute lymphoblastic leukemia in first remission. Bone Marrow Transplant 52, 470–472 (2017). https://doi.org/10.1038/bmt.2016.307
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