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Survival outcomes in older patients with acute myeloid leukemia (AML) are historically poor, mainly due to factors such as poor tolerance to conventional chemotherapy and a higher incidence of cytogenetic risk in this population.1 Lower-intensity venetoclax-based approaches have shown promising results in older patients with AML who are unfit for intensive chemotherapy (IC). However, the type of induction therapy used in older patients with newly diagnosed AML who are fit for allogeneic hematopoietic stem cell transplantation (allo-HSCT) is controversial and the impact on outcomes remains largely unknown.1
Short et al.1 recently published a retrospective study in Blood Advances evaluating the impact of the type of induction therapy in older patients with newly diagnosed AML after allo-HSCT. We are pleased to present the key highlights from this study here.
This was a retrospective study in older patients with newly diagnosed AML undergoing allo-HSCT at the University of Texas MD Anderson Cancer Center between November 2012 and July 2021. The study design is shown in Figure 1.
Figure 1. Study design*
allo-HSCT, allogeneic hematopoietic stem cell transplantation; AML, acute myeloid leukemia; CR, complete remission; CRi, CR with incomplete recovery; IC, intensive chemotherapy; LIT, lower intensity therapy; MLFS, morphologic leukemia-free state; VEN, venetoclax.
*Data from Short, et al.1
Responses, defined by the European LeukemiaNet consensus guidelines were as follows:
A total of 127 patients were included, of which 44 patients received IC, 29 received low-intensity therapy (LIT) without venetoclax (VEN), and 54 patients received LIT with VEN. Patients in the IC cohort versus LIT without VEN or LIT with VEN were younger and more likely to have an Eastern Cooperative Oncology Group performance status of 0 at the time of AML diagnosis (p = 0.02) and de novo AML (p = 0.03). Most patients had intermediate or adverse-risk AML; however, two patients had core-binding factor AML in the IC cohort (Table 1).
Table 1. Baseline characteristics*
Characteristic, % (unless otherwise stated) |
IC without VEN |
LIT without VEN |
LIT + VEN |
p value† |
---|---|---|---|---|
Median age (range), years |
63 (60–76) |
67 (61–75) |
68 (60–77) |
<0.0001 |
ECOG PS |
|
|
|
|
0 |
34 |
10 |
17 |
0.06 |
1 |
61 |
72 |
72 |
— |
2 |
5 |
17 |
11 |
— |
AML type |
|
|
|
|
de novo |
80 |
69 |
56 |
0.04 |
Secondary |
20 |
31 |
44 |
— |
ELN 2017 risk |
||||
Favorable‡ |
20 |
14 |
19 |
0.66 |
Intermediate |
36 |
38 |
26 |
— |
Adverse |
43 |
48 |
56 |
— |
Mutations |
|
|
|
|
NPM1 |
27 |
24 |
22 |
0.85 |
FLT3-ITD |
20 |
24 |
11 |
0.26 |
IDH1/IDH2 |
25 |
10 |
26 |
0.22 |
KRAS/NRAS |
11 |
10 |
22 |
0.23 |
RUNX1 |
7 |
3 |
22 |
0.02 |
ASXL1 |
9 |
0 |
17 |
0.06 |
TP53 |
18 |
21 |
13 |
0.62 |
AML, acute myeloid leukemia; ECOG PS, Eastern Cooperative Oncology Group performance status; ELN, European LeukemiaNet; IC, intensive chemotherapy; LIT, lower-intensity therapy; MLFS, morphologic leukemia-free state; VEN, venetoclax. |
The median duration of follow-up post allo-HSCT was 59.8 months, 76.8 months, and 20.3 months in the IC, LIT without VEN, and LIT + VEN cohorts, respectively. The 2-year CIR, NRM, RFS, and OS for all three cohorts are shown in Figure 2.
Figure 2. Outcomes by induction therapy*
CIR, cumulative incidence of relapse; IC, intensive chemotherapy; LIT, lower-intensity therapy; NRM, non-relapse mortality; OS, overall survival; RFS, relapse-free survival; VEN, venetoclax.
*Data from Short, et al.1
Figure 3 shows that the 2-year RFS and OS were higher in the LIT + VEN cohort compared with IC and LIT without VEN cohorts in patients with:
In addition, patients with TP53 mutations in the LIT + VEN cohort also showed improved RFS and OS compared with those in the IC and LIT without VEN cohorts (RFS, p = 0.05; OS, p = 0.02).
Figure 3. Relapse-free survival and overall survival in patients with A MRD negative status and B adverse-risk AML*
AML, acute myeloid leukemia; IC, intensive chemotherapy; LIT, lower-intensity therapy; MRD, minimal residual disease; OS, overall survival; RFS, relapse-free survival; VEN, venetoclax.
*Adapted from Short, et al.1
In a univariate analysis, HSCT comorbidity index (HSCT-CI) ≥3 was associated with significantly increased risk of relapse (sub-distributional hazard ratio [SHR], 2.21; p = 0.03).
In a multivariate analysis, only HSCT-CI ≥3 was associated with inferior RFS (HR, 1.90; p = 0.02) and OS (HR, 2.09; p = 0.01).
This retrospective study showed favorable RFS and OS with LIT + VEN in older patients with newly diagnosed AML fit for allo-HSCT, providing a rationale to consider LIT + VEN in this population. The study also highlighted better survival outcomes with LIT + VEN compared with IC induction for patients with adverse-risk AML. This appears to be the largest cohort assessing LIT + VEN after allo‑HSCT and comparing IC and LIT + VEN in older allo-HSCT eligible patients. However, the findings of the study should be considered with several caveats such as confounding factors due to younger and fitter patients in the IC cohort and inclusion of patients who underwent allo-HSCT in first remission. The patients in the cohorts were treated in different time periods, and this may have impacted the outcomes due to advances in treatment for relapsed/refractory AML, better supportive care, and changes in allo-HSCT procedures.
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