The Influence of Measurable Residual Disease and Post-Remission Treatment to the Prognosis of ALL

ObjectiveAcute lymphoblastic leukemia(ALL) is a heterogeneous disease and allo-HSCT is still the important way to cure it. Considering the severe comorbidities of HSCT, it's worth to identify risk stratification of the ALL accurately to determine who would benefit from HSCT. In our research, we analysis the relationship of post-remission treatment(PRT) and outcome of ALL, try to choice suitable therapy based on dynamic measurable residual disease(MRD).

MethodWe collect newly diagnosis ALL patients from january 1,2014 to December 20, 2021 from Shandong Provincial Hospital, Yantai Yuhuangding Hospital, and Qingdao University Affiliated Hospital. Based on the different PRT, chemotherapy or transplantation, patients were divided into CMT group and SCT group. MRD results based on flow cytometry during the course of therapy were collected and the patients were divided into four groups(A: MRD negative after 1 course of chemotherapy(MRD1-/MRD2±/MRD3±); B: MRD negative after 2 course of chemotherapy(MRD1+/MRD2-/MRD3±); C: MRD negative after 3 course of chemotherapy(MRD1+/MRD2+/MRD3-); D: MRD still positive after 3 course of chemotherapy(MRD1+/MRD2+/MRD3+)). Fisher's exact test and Mann-Whitney U test were used for analyse variables between different groups. Kaplan-Meier method was used to estimate survival. Cox proportional hazards regression model was use to analyze the risk factors for time-event variables. P<0.05 was considered as statistically significant.

Results We identified 404 patients meeting the inclusion criteria. At last, 182 B-ALL patients were fulfill the selection criteria. 112 were classified in CMT group, and 70 in SCT group. The results of uni-variate analysis showed that patients who achieved morphological CR after first induction chemotherapy(P=0.000 and P=0.000), reached MRD1<0.01%(P=0.019 and P=0.004), MRD2<0.01%(P=0.001 and P=0.000), MRD3<0.01%(P=0.000 and P=0.000), classified as standard-risk by non-cytogenetic risk stratification(P=0.042 and P=0.042), or grouped in SCT group(P=0.000 and P=0.000) had better OS and DFS, while age over 35 had poor OS(P=0.021). Other factors such as cytogenetic risk stratification, sex, white blood count and philadelphia chromosome had no effect on OS. Multiple analysis showed that only MRD3<0.01(P=0.024) and the PRT regimen(P=0.021) were independent prognostic factors for OS and PFS.

Then, we further analysis the recurrence of the patients. The median time of relapse in CMT group and SCT group was 6 months and 16.5 months, and the median OS is 14 months and 31.5 months, respectively. The relapse rate in CMT group was 59.82%(67/112), while SCT group was 22.86%(16/70). Total of 75 patients accept re-induction and statistically insignificance in remission rate (68.85% vs 71.43%) and mortality rate(59.02% vs 71.43%) between the two groups.

Next, we analyse the relationship between dynamic MRD level and prognosis of ALL. Results showed that early achievement of MRD negative had better prognosis. The 5-year OS of the four groups(A, B, C, and D) were 64.75%,52.15%,43.85% and 24.32%, and the 5-year DFS were 50.17%,52.27%,17.38% and 7.35%, respectively(P=0.000). Then we further in-depth analysis data of MRD1- patients. Interesting, patients in CMT and SCT group with MRD1- have comparable mortality(29.73% vs 25%, P=0.673) and NRM(5.41% vs 7.14%, P=0.530). Though relapse rate is obviously higher in CMT than SCT groups(45.95% vs 21.43%, P=0.041), the 5-year OS in CMT groups was as good as SCT groups(60.9% vs 71.9%, P=0.176). And the approaching survival may benefit from the high re-remission rate in CMT group compared with SCT group(64.71% vs 33.33%). The same results were also confirmed in the MRD1+ patient(B, C and D), where the recurrence rate(66.67% vs 23.81%, P=0.000) and recurrence related mortality rate(44.00% vs 14.29%, P=0.001) were significantly higher in CMT patients than SCT group, and HSCT can overcome relapse and its associated mortality in MRD1+ patient.

ConclusionDynamic MRD has strong prognosis significance during the course of treatment in ALL. Patients who achieve MRD1- after initial induction have similar OS despite accept HSCT or not. Though CMT group has a higher recurrence rate, the remission rate of re-induction treatment also high. With the development of new agents and MRD detection technology, accurately distinguish high-risk patients based on MRD would help us to make better treatment decisions.

No relevant conflicts of interest to declare.