Dynamics of Minimal Residual Disease Defines a Novel Risk-Classification and the Role of Allo-HSCT in Adult Ph-Negative B Cell Acute Lymphoblastic Leukemia

Background： MRD is a well-known prognostic indicator for comprehensive evaluation of adult Ph-negative acute B cell lymphoblastic leukemia (Ph-B-ALL), but previous studies have mostly focused on the prognostic significance of MRD status at a single time point (eg, after induction or consolidation therapy). The implementation of dynamic MRD for risk classification and decision-making for allo-HSCT remains vague. Therefore, it is necessary to explore the prognostic and therapeutic significance of dynamic MRD monitoring by multi-parameter flow cytometry (MFC-MRD) in Ph-B-ALL during early induction period.

Method: We collected FCM-MRD on day 14 (MRD1), 24 (MRD2), and 45 (MRD3) of Ph-negative B-ALL patients (n=134) in Precision-Classification-Directed-Target-Total-Therapy-ALL-2016(PDT-ALL-2016) cohort of Nanfang Hospital. Following the protocol, the population was stratified into standard-risk (SR, MRD1<1% and MRD2<0.1%), medium-risk (MR, MRD1>1% but MRD2<0.1%), and high-risk (HR, MRD2>0.1%) based on the dynamic MRD data. Then, the long-term outcome was assessed, as well as the impact of allo-HSCT on different risk groups.

Result: With a median of 3.65 years follow-up (95%CI: 3.037~4.263), there are 61.9% (83/134) of patients achieved MRD-negativity before consolidation therapy. However, among these patients, 25.3% (21/83) relapsed, and 30.1% (25/83) died within the observed period. As expectedly, Kaplan-Meier survival analysis revealed that patients in the HR group experienced a worse outcome, with 3-year OS and EFS rates of 51.8 ± 8.3% and 37.6 ± 8.2%, respectively, compared to the SR group (73.3 ± 5.9% and 63.0 ± 6.3%, respectively) and the MR group (61.5 ± 10.8% and 51.9 ± 11.3%, respectively). Multivariate analysis indicated that integrated dynamics MRD is an independent factor for EFS (P=0.001) and OS (P=0.022). Of note, compared with pediatric-inspired chemotherapy, allo-HSCT significantly improves the survival of the HR cohort (P<0.001), but not in MR (P=0.17) and SR (P=0.81).

Conclusion: Collectively, our study suggests that integrated dynamic MRD defines a novel risk classification and highlights the benefits of allo-HSCT in adult patients with Ph-negative ALL.

Trial registration: The trial is registered with www.clinicaltrials.gov identifier NCT03564470.

Figure legend A. Flow diagram of patients in trial

B. OS, EFS and CIR for all patients based on novel risk-stratification

C. Comparison between chemotherapy and allo-HSCT with OS in high risk groups, medium-risk and standard risk

No relevant conflicts of interest to declare.