Professor Liu Qiqi's team: The application of dynamic monitoring of MRD in the first remission and treatment of low-risk AML patients and its significance to clinical prognosis

Treatment strategies for acute myeloid leukemia (AML) typically include induction therapy and post-remission therapy
.

According to previous studies, about 70% of young adult patients with AML can achieve morphological complete remission (CR) after receiving standard "3+7" induction therapy
.

Patients who achieve CR usually receive post-remission therapy to prevent relapse, usually with several consolidation chemotherapy regimens with or without hematopoietic stem cell transplantation (HSCT)
.

The choice of treatment options for patients with AML after remission currently depends on the risk stratification of cytogenetics and molecular markers
.

According to the molecular/cytogenetic risk stratification system, AML patients were divided into three groups: low-risk, intermediate-risk, and high-risk
.

For patients with low-risk AML, the treatment regimen after first remission (CR1) is usually intensive chemotherapy
.

However, the choice of post-remission treatment options for such patients is still controversial.
For example, previous studies have shown that compared with intensive chemotherapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) and autologous hematopoietic stem cell transplantation (auto-HSCT) Better survival benefit for low-risk AML patients with CEBPA double mutation
.

Therefore, for patients with low-risk AML, other factors need to be considered to allow for more refined treatment stratification of patients with low-risk AML
.

An increasing number of studies have shown that patients with persistent measurable residual disease (MRD) have a high risk of recurrence and poor prognosis, so MRD is an important consideration in the choice of post-remission treatment options
.

However, the optimal timing of post-remission treatment decisions remains inconclusive
.

Based on this, Prof.
Qiqi Liu and his team from Nanfang Hospital of Southern Medical University retrospectively analyzed the effect of dynamic monitoring of MRD after CR1 and post-remission treatment on prognosis of young adult patients with low-risk AML
.

Research methods From January 1, 2012 to December 30, 2017, researchers continuously screened 642 newly diagnosed low-risk AML patients from the South China Blood Specialist Alliance database, and finally included 403 patients who achieved CR1
.

The definition of low-risk AML was based on NCCN criteria and included NPM1 mutations, RUNX1-RUNX1T1, CBFB-MYH11, and CEBPA double mutations
.

According to the different treatment regimens after remission, patients were divided into three groups: chemotherapy group (CMT), auto-HSCT group and allo-HSCT group
.

Patients without prior HSCT who received at least two cycles of consolidation chemotherapy were included in the CMT group; patients who relapsed after chemotherapy and subsequently received HSCT were included in the CMT group
.

Inclusion criteria: ①14-60 years old; ②Low-risk AML; ③CR1
.

Because there are fewer patients with FLT3-ITD allele ratio test results, and patients with FLT3-ITD mutations have not yet reached consensus on the use of sorafenib, there will be inevitable bias, so patients with NPM1/FLT3-ITD mutations are not included studies (n=85)
.

The last follow-up date was May 31, 2021
.

The primary endpoint was the 5-year cumulative overall survival (OS) rate, with secondary endpoints including cumulative disease-free survival (DFS) rate, cumulative recurrence rate (CIR), and non-relapse mortality (NRM) as well as graft-versus-host disease-free and recurrence-free survival rate (GRFS)
.

Results 1 Patient characteristics A total of 403 patients were included in the study, 173 in the CMT group, 92 in the auto-HSCT group, and 138 in the allo-HSCT group
.

In this study, MRD was the causal variable, so to ensure MRD data integrity, 77 patients with missing MRD data within 3 chemotherapy cycles were excluded
.

Among the 77 patients, 40 (18.
8%) in the CMT group, 14 (13.
2%) in the auto-HSCT group and 23 (14.
3%) in the allo-HSCT group (p=0.
335), the data missing rate was among the three groups No statistical difference between
.

In the allo-HSCT group, 61 patients received a matched sibling donor (MSD) transplant and 77 received a replacement donor transplant, of the latter, 64 were haploid donor (HID) transplants and 10 were Matched unrelated donor (MUD) transplants and 3 cases were umbilical cord blood transplants
.

The median age of enrolled patients was 36 (14-60) years, 44 (16-60) years in the CMT group, 35 (17-55) years in the auto-HSCT group, and 33 (14) years in the allo-HSCT group.
-60) years old
.

The patients in the CMT group were older than those in the auto-HSCT and allo-HSCT groups, with statistical significance (p=0.
002 and p<0.
001, respectively)
.

The proportion of patients requiring two cycles to achieve a CR was higher in the allo-HSCT group compared with the CMT group (p=0.
026)
.

In the allo-HSCT group, more patients had MRD+ (MRD1+) after the first chemotherapy, MRD+ (MRD2+) after the second chemotherapy, and MRD+ (MRD3+) after the third chemotherapy (p=0.
001, p=0.
006, p <0.
001)
.

The basic characteristics of the three groups of patients are shown in Figure 1
.

Figure 12 Survival analysis The median time from CR1 to recurrence was 10.
4 (5.
2-50.
7) months in the enrolled patients, 9.
7 (5.
2-50.
7) months in the CMT group, and 11.
0 (6.
1-38.
2) months in the auto-HSCT group, The allo-HSCT group was 14.
0 (5.
8-47.
2) months (p=0.
018)
.

Compared with the CMT group, the time from CR1 to relapse was longer in the allo-HSCT group (p=0.
006), but the allo-HSCT versus auto-HSCT (p=0.
181) or auto-HSCT versus CMT group ( p=0.
191) was not statistically different
.

The 5-year CIR was 31.
3% (95% CI, 24.
5-38.
3%) in the CMT group, 20.
6% (95% CI, 13.
1-29.
5%) in the auto-HSCT group, and 13.
1% (95% CI, 13.
1-29.
5%) in the allo-HSCT group.
8.
1-19.
3%) (p<0.
001) (Fig.
2a)
.

Multivariate analysis showed that CIR was significantly lower in the allo-HSCT group than in the CMT group (HR, 0.
176 [95%CI, 0.
096–0.
324]; p<0.
001) and the auto-HSCT group (HR, 0.
330 [95%CI, 0.
170– 0.
639]; p=0.
001), and the auto-HSCT group also had a lower CIR than the CMT group (HR, 0.
535 [95% CI, 0.
320–0.
893]; p=0.
017)
.

The 5-year cumulative NRM was 1.
2% (95%CI, 0.
2-3.
8%), 3.
3% (95%CI, 0.
9-8.
5%), and 11.
6% (95%CI, 0.
9-8.
5%) in the CMT, auto-HSCT, and allo-HSCT groups, respectively.
6.
9-17.
6%) (p<0.
001) (Fig.
2b)
.

The NRM of the allo-HSCT group was significantly higher than that of the CMT group (HR, 10.
605 [95%CI, 2.
449–45.
923]; p=0.
002) and the auto-HSCT group (HR, 3.
710 [95%CI, 1.
080–12.
744]; p= 0.
037), but there was no statistical difference between the auto-HSCT and CMT groups (HR, 2.
858 [95% CI, 0.
478–17.
090]; p=0.
250) (Fig.
2b)
.

The 5-year DFS rate was 67.
5% (95%CI, 60.
0-74.
0%) in the CMT group, 76.
1% (95%CI, 66.
0-83.
6%) in the auto-HSCT group, and 75.
3% (95%CI) in the allo-HSCT group , 67.
2-81.
7%) (p=0.
166) (Fig.
2c), in univariate analysis, the 5-year DFS rates of the 3 groups were not statistically different
.

However, multivariate analysis showed that the allo-HSCT group (HR, 0.
372 [95%CI, 0.
234–0.
591]; p<0.
001) and the auto-HSCT group (HR, 0.
595 [95%CI, 0.
360–0.
984]; p=0.
043 ) has a better DFS than the CMT group
.

The 5-year OS rates in the three groups were 79.
8% (95%CI, 73.
0–85.
0%), 81.
3% (95%CI, 71.
7–88.
0%), and 79.
7% (95%CI, 72.
0–85.
5%) (p=0.
892) ) (Fig.
2d)
.

In univariate and multivariate analyses, choice of postremission treatment regimen was not an independent factor for OS
.

In multivariate analysis, higher white blood cell count (≥50 × 109/L), CR with two cycles of chemotherapy, MRD2+ and MRD3+ were risk factors for DFS and OS
.

Figure 23.
Subgroup analysis of dynamic monitoring of MRD.
To explore the association between MRD dynamically monitored by multiparameter flow cytometry (MFC), choice of post-remission treatment regimen, and clinical outcomes in low-risk AML, researchers analyzed MRD1, MRD2, and MRD3 A subgroup analysis was performed on the dynamic changes
.

The patients were divided into four subgroups: (I) Subgroup A, who achieved MRD-(MRD1-/MRD2-/MRD3-) after 1 course of chemotherapy; (II) Subgroup B, who achieved MRD-(MRD-(MRD-(MRD1-/MRD2-/MRD3-) after 1 course of chemotherapy); MRD1+/MRD2-/MRD3−); (III) Subgroup C, achieved MRD- after 3 cycles of chemotherapy (MRD1+/MRD2+/MRD3−); (IV) Subgroup D, continued MRD+ (MRD1+/MRD2+) after 3 cycles of chemotherapy /MRD3+) or MRD compound positivity (from MRD- to MRD+)
.

In subgroup A and subgroup B, there was no significant difference in OS between CMT, auto-HSCT, and allo-HSCT groups (p=0.
340 and p=0.
627, respectively)
.

However, in both subgroups, patients in the CMT and auto-HSCT groups had better GRFS than allo-HSCT
.

In subgroup C, the DFS rate in the allo-HSCT group was better than that in the CMT group (p=0.
009)
.

In subgroups A, B, and C, the choice of post-remission treatment regimen did not have a significant effect on OS
.

However, in subgroup D, the OS of the allo-HSCT group was better than that of the CMT and auto-HSCT groups (p=0.
011 and p=0.
029, respectively)
.

Specifically as shown in Figure 3
.

Figure 3 Study Conclusions This study is the first attempt to explore the best options for post-remission treatment for low-risk AML patients based on the results of dynamic monitoring of MRD
.

The results of the study show that for patients who can achieve MRD- within 3 chemotherapy cycles, intensive chemotherapy after the first remission is recommended; for patients with continuous MRD+ or MRD re-positive after 3 chemotherapy cycles, allo-HSCT treatment is recommended
.

This retrospective study still has certain shortcomings, such as some unavoidable biases; the imbalance of patient age between the CMT and HSCT groups; in the subgroup analysis, the number of patients in some subgroups was too small
.

In conclusion, this study also needs data support from prospective clinical trials
.

Reference: Sijian Yu, Tong Lin, Danian Nie, et al.
Dynamic assessment of measurable residual disease in favorable-risk acute myeloid leukemia in first remission, treatment, and outcomes.
Blood Cancer J.
2021 Dec 6;11(12): 195.
doi: 10.
1038/s41408-021-00591-4.
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