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Most younger patients with acute myeloid leukemia (AML) achieve a complete remission (CR) after induction chemotherapy but require post-remission treatment (PRT) to prevent relapse. PRT decisions are mostly based on risk-stratification using cytogenetics and molecular markers but selecting the optimal PRT, particularly for patients with intermediate risk AML, remains a challenge due to contradictory conclusions from previous studies. As such, there is a need for additional predictive factors to optimize PRT selection. Earlier reports have indicated a possible role for measurable residual disease (MRD), although the optimal timing of MRD assessment to guide treatment selection is widely debated. Here we summarize a report by Yu and colleagues which aimed to explore PRT choices based on dynamic MRD for younger patients with intermediate risk AML.1
A total of 549 younger patients (median age, 37 years; range, 14−60 years) with de novo intermediate risk AML in first CR (CR1) were included in the study. Exclusion criteria included:
Patients were classified into three groups according to PRT:
MRD was assessed in the bone marrow after induction therapy, after each cycle of PRT, and then at 2, 3, 4, and 6-month intervals during the first, second, third, and fourth/fifth years after PRT, respectively. To explore the association between MRD dynamics and PRT selection, subgroup MRD analyses were performed after one, two and three courses of chemotherapy, and patients were classified into the following subgroups:
Evaluation endpoints included relapse, survival, and transplant-related mortality.
Selected patient characteristics are shown in Table 1. In the allo-SCT group, half of the patients received matched sibling donors and one third of patients received haploidentical donors. Over half of patients received first induction therapy with idarubicin hydrochloride and cytarabine (IA), and most patients received intermediate- or high-dose cytarabine as second induction or first consolidation therapy.
Table 1. Selected patient characteristics according to PRT group*
Characteristic |
CMT |
Auto-SCT |
Allo-SCT |
p value |
---|---|---|---|---|
Age, median (range), years |
47 (14–60) |
33.5 (15–60) |
35 (14–60) |
<0.001 |
First induction therapy, % |
||||
DA |
27.3 |
25.0 |
21.5 |
0.34 |
IA |
57.8 |
60.3 |
67.4 |
|
Other |
14.9 |
14.7 |
11.1 |
|
Second induction therapy or first consolidation therapy, % |
||||
DA |
9.1 |
6.9 |
5.7 |
0.81 |
IA |
9.1 |
11.2 |
7.5 |
|
3 + 3 |
31.2 |
26.7 |
28.7 |
|
Intermediate- /high-dose cytarabine |
44.2 |
48.3 |
51.6 |
|
Other |
6.5 |
6.9 |
6.5 |
|
Cycles of consolidation therapy, median (range) |
4 (3–7) |
3 (3–5) |
2 (1–4) |
NA |
Duration from CR1 to transplant, median (range), months |
NA |
5.9 (5.4–9.6) |
3.9 (2.8–7.7) |
<0.001 |
Number of cycles to CR, % |
||||
1 |
81.8 |
83.6 |
77.8 |
0.34 |
2 |
18.2 |
16.4 |
22.2 |
|
MRD1, % |
||||
Positive |
52.6 |
55.2 |
77.1 |
<0.001 |
Negative |
47.4 |
44.8 |
22.9 |
|
MRD2, % |
||||
Positive |
33.8 |
28.4 |
47.3 |
0.001 |
Negative |
66.2 |
71.6 |
52.7 |
|
MRD3, % |
||||
Positive |
25.3 |
22.4 |
37.6 |
0.002 |
Negative |
74.7 |
77.6 |
62.4 |
|
3 + 3, daunorubicin hydrochloride or idarubicin hydrochloride, 10 mg/m2 per day on Days 1 to 3 and cytarabine, 2 g/m2 twice daily on Days 1 to 3; allo-SCT, allogeneic stem cell transplant; auto-SCT, autologous stem cell transplant; CMT, chemotherapy; CR, complete remission; CR1, first CR; DA, daunorubicin hydrochloride and cytarabine; IA, idarubicin hydrochloride and cytarabine; MRD1, measurable residual disease after one course of CMT; MRD2, MRD after two courses of CMT; MRD3, MRD after three courses of CMT; NA, not applicable. |
A total of 146 patients had relapsed at last follow-up. The key relapse and survival outcomes according to PRT group is presented in Table 2.
Table 2. Relapse and survival outcomes by PRT group*
Outcome |
CMT |
Auto-SCT |
Allo-SCT |
---|---|---|---|
Time from CR1 to relapse, median (range), months |
9.9 |
10.9 |
13.0 |
5-year cumulative incidence of relapse, % (95% CI) |
49.4 |
27.6 |
13.6 |
5-year cumulative incidence of transplant-related mortality, % (95% CI) |
1.3 |
3.4 |
10.4 |
5-year LFS rate, % (95% CI) |
49.3 |
69.0 |
76.0 |
5-year OS rate, % (95% CI) |
57.6 |
75.0 |
78.1 |
5-year GRFS rate, % (95% CI) |
49.3 |
69.0 |
56.5 |
Allo-SCT, allogeneic stem cell transplant; auto-SCT, autologous stem cell transplant; CI, confidence interval; CMT, chemotherapy; CR1, first complete remission; GRFS, graft-versus-host-disease-free, relapse-free survival; LFS, leukemia-free survival; OS, overall survival. |
According to multivariate analysis, requiring two cycles of chemotherapy to achieve CR (versus one cycle) and MRD after three cycles of chemotherapy were risk factors for relapse, LFS, and OS in the entire population. Allo-SCT had a favorable association with relapse, LFS, and OS, compared with auto-SCT or CMT.
In the entire population, post-remission treatment with allo-SCT and auto-SCT were advantageous with respect to incidence of relapse, LFS, and OS, compared with chemotherapy. Whilst LFS and OS were comparable for the allo-SCT and auto-SCT groups, allo-SCT had a lower incidence of relapse but higher transplant-related mortality than auto-SCT.
Based on the results of the dynamic MRD subgroup analysis, the authors suggest that chemotherapy and auto-SCT might be preferable for patients who are persistently MRD negative, whereas they recommend allo-SCT for patients who are persistently MRD positive or have recurrent MRD. Auto-SCT might be favored before allo-SCT for patients who are MRD negative after two courses of chemotherapy, whereas allo-SCT might be favored for patients who are MRD negative after three courses of chemotherapy.
The authors note the retrospective nature of this study, and a prospective multicenter trial is underway to validate these findings.
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