The Prognostic Significance of 1-Year Persistent MRD Negativity in Chinese ALL Patients: 5-Year Follow-up Results from RJ-ALL 2014 Trial

Abstract

Background Minimal residual disease (MRD) monitoring is an important predictor of outcomes in acute lymphoblastic leukemia (ALL), and flow cytometry is widely used to monitor MRD with a detection depth of 10 -4~10 -5. Post induction MRD is the most commonly applicated timepoint for risk stratification of ALL. About half of the patients (pts) with post induction CR/CRi achieved simultaneous MRD negativity, however, among them some pts subsequently relapse. Thus, how to better interpret the MRD results has always been a topic of interest among clinicians. Hence, in this report, we monitored MRD at different timepoints and focus on the 1-year persistent MRD negativity and its impact on the prognosis. Method In this prospective long-term follow-up study, we analyzed 202 cases of Ph/BCR-ABL1 negative BCP-ALL. All pts were treated with RJ-ALL 2014 protocol as follow: The induction regimen was VDPCP, the consolidation regimen was hyper-CVAD + Pegasparagase (PEG) and the maintenance regimen was POMP + PEG. CNS prophylaxis was integrated. Pts eligible for allogeneic hematopoietic stem cell transplantation (allo-HSCT) were recommended to transplant. MRD was monitored by 8-color flow cytometry. MRD negativity is defined as MRD < 10 -4. MRD monitoring was performed at the end-of-induction (EOI), the 3 rd month and every 3 months afterwards during 5 years. 1-year persistent MRD negativity (1-yr-MRDneg) was defined as sustained 1-year MRD negative from EOI or 3 rd month. Results From May 2014 to Nov 2021, a total of 202 pts were enrolled. The median age of pts at diagnosis was 35 years (range 14~65). After induction, 179 / 193 (92.7%) pts achieved CR/CRi, among them 102 (57%) pts were MRD negative (MRDneg). There were 9 (4.5%) early death during induction due to hemorrhage or infection. At the third month, 171 pts were in CR/CRi, among them, 120 (75%) of the 160 evaluable pts were MRDneg. At one year, 123 pts were in CR/CRi, among them, 48 (70.6%) of the 68 evaluable pts were MRDneg. By Jul 2023, the median follow-up time was 56 months. Ten pts were lost to follow-up. The 5-yr OS rate is 52.6% and the 5-yr RFS rate is 50.7%. Regarding the EOI MRD status, the MRDneg group trend to have better OS (5-yr OS 63.6% vs 51.2%, p=0.128) and RFS (5-yr RFS 53.4% vs 48%, p=0.088) compare to MRD positive (MRDpos) group. Regarding the MRD status at the third month, the OS (5-yr OS 66.9% vs 38.4%, p=0.000) and RFS (5-yr RFS 64.6% vs 28.2%, p=0.000) of MRDneg group was significantly better than that of MRDpos group. Totally, 80 pts received allo-HSCT, among them, 78 pts achieved CR and 49 pts were MRDneg before HSCT. After HSCT, 18 pts relapsed and 22 pts died, among them 7 pts died of relapse and 15 pts dead of treatment toxicity. For transplanted pts, the 5-yr OS rate is 65% and the 5-yr RFS rate is 58.6%. We further analyzed the 1-year persistent MRD status of non-transplanted pts. Among 113 non-transplanted pts, 68 pts had 1-year complete MRD data. Of which 48 pts had 1-yr-MRDneg and 20 pts had rising MRD within 1 year. For pts with 1-yr-MRDneg, 5-yr OS rate is 86.9% and 5-yr RFS rate is 85.7%. For pts with rising MRD, 5-yr OS rate is 11.3% and 5-yr RFS rate is 16.7%. Comparing their survival with transplanted pts we found that the OS and RFS of non-transplanted 1-yr-MRDneg pts were significantly better than allo-HSCT (OS p<0.01, RFS p<0.01), and allo-HSCT were significantly better than non-transplanted pts with rising MRD within 1 year (OS p<0.01, RFS p<0.01) (figure 1). Conclusion In this long-term follow-up study, we found that in Ph/BCR-ABL1 neg patients, 1-year persistent MRD negativity is a stronger prognostic predictor than EOI or 3 rd month MRD negativity. Non-transplanted pts with 1-yr persistent MRD negativity have better 5-year survival than those who receive allo-HSCT, suggesting that pts with 1-yr persistent MRD negativity may be spared from allo-HSCT.