Association of minimal residual disease with clinical outcomes in Philadelphia chromosome positive acute lymphoblastic leukemia in the tyrosine kinase inhibitor era: A systemic literature review and meta-analysis.

Wanhua Zhang,Erguai Jang,Stefano Tiziani

doi:10.1371/journal.pone.0256801

Wanhua Zhang, Erguai Jang + Show 1 more

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https://doi.org/10.1371/journal.pone.0256801

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Abstract

Minimal residual disease (MRD) appeared to be a potent prognostic indicator in patients with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), with potential value in informing individualized treatment decisions. Hence, we performed herein a systemic literature review and meta-analysis to comprehensively address the prognostic value of MRD in Ph+ ALL. Systematic literature review was conducted in PubMed, Embase, and Cochrane databases with the data access date up to September 23, 2020. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated with fixed-effects or random-effects models. Furthermore, subgroup analyses were performed to assess the robustness of the associations. 27 studies with a total number of 3289 patients were eligible for this meta-analysis. Combined HRs suggested that MRD positivity was associated with inferior event-free survival (EFS) (HR = 2.00, 95% CI 1.77–2.26) and overall survival (OS) (HR = 2.34, 95% CI 1.86–2.95). The associations remained statistically significant in subgroup analyses including age group, MRD timing, disease status at MRD, MRD cutoff level, et al. Our findings suggested MRD as a potent clinical tool for assessing the prognosis of Ph+ ALL. Further studies using MRD-based risk stratification might help optimize individualized treatment strategies for Ph+ ALL patients.

Highlights

Philadelphia (Ph) chromosome is the der(22) product of the reciprocal translocation between 9q34 and 22q11.2, which generates the BCR-ABL1 fusion gene [1]
After screening the title and abstract of each record, 236 records were included in the full text screen. 209 records were discarded for the following reasons: not investigating the correlation between Minimal residual disease (MRD) and outcomes (n = 166), including nonTKIs treated patients (n = 7), less than 50 patients (n = 15), insufficient data to attain hazard ratios (HRs) and 95% confidence intervals (CIs) (n = 10), overlapped cohorts (n = 11)
Sensitivity analyses revealed that no single study significantly altered the results (Fig 4). In this meta-analysis, we demonstrated that positive MRD was associated with worse clinical outcomes in Ph+ acute lymphoblastic leukemia (ALL) patients

Summary

Introduction

Philadelphia (Ph) chromosome is the der(22) product of the reciprocal translocation between 9q34 and 22q11.2, which generates the BCR-ABL1 fusion gene [1]. It can be detected in 25– 40% of adult patients with acute lymphoblastic leukemia (ALL) [2, 3]. Philadelphia chromosome was associated with a dismal prognosis, with long-term survival rates of less than 20%, and the only curative possibility was based on intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) [4–6]. Association of MRD with prognosis in Ph+ ALL kinase inhibitors (TKIs) has remarkably improved the treatment response and long-term survival of Ph+ ALL patients [7–12]. Prediction and intervention before hematological relapse are important in reducing the incidence of relapse and improving clinical outcomes

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