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Patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) have no standard treatments and have dismal outcomes with 10–20% long-term survival. Continuing intensive chemotherapy (IC) in these patients becomes challenging due to disease progression or subsequent therapy, including stem cell transplantation (SCT). Thereby, novel, lower intensity chemotherapies are warranted. Venetoclax (VEN)-based lower intensity regimens are standard treatments for older or unfit patients with AML and are potentially efficacious in younger patients as well. However, there is no evidence of how venetoclax-based lower intensity regimens compare with IC.
The AML Hub has previously reported an expert interview describing the real-word experience of R/R AML treatment with venetoclax plus hypomethylating agents (HMAs) and an article on the effectiveness of decitabine (DEC) + VEN in patients with high-risk AML and myelodysplastic syndromes (MDS). Here we present the key findings of a recent study by Maiti et al.1, published in Cancer, comparing the outcomes of low-intensity DEC + VEN versus IC in patients with R/R AML.
This was a retrospective, cohort study consisting of two cohorts, the 10-day decitabine and venetoclax (DEC10-VEN) cohort from the prospective phase II trial of DEC10-VEN (NCT03404193), and the IC cohort. Patients enrolled in both the DEC10-VEN and IC cohorts were adults aged >18 years with an Eastern Cooperative Oncology Group performance status (ECOG PS) of ≤ 3.
Treatment regimens:
The included IC regimens comprised of the following therapies given intravenously:
Outcomes included:
The best matched patients using propensity scores between the two cohorts is shown in Figure 1.
Figure 1. Propensity score matching*
AML, acute myeloid leukemia; IC, intensive chemotherapy; DEC10-VEN, 10-day decitabine with venetoclax; R/R, relapsed or refractory.
*Adapted from Maiti et al.1
†Propensity score matched for age, Eastern Cooperative Oncology Group performance status (ECOG PS), number of therapies, AML (primary refractory vs relapsed), first complete remission (CR1) duration, prior stem cell transplantation (SCT), European LeukemiaNet cytogenetic risk category, FLT3-ITD/TKD (mutated vs wild type), TP53 (mutated vs wild type).
The median age was 64 years (range, 18–85) and 58 years (range, 19–80) in the DEC10-VEN and IC cohorts, respectively. Patients received a median of two cycles (range, 1–16) and one cycle (range, 1–5) of therapy in the DEC10-VEN and IC cohorts, respectively. The baseline characteristics were well balanced between the two cohorts (Table 1).
Table 1. Baseline characteristics*
AHD, antecedent hematologic disorder; AML, acute myeloid leukemia; DEC10-VEN, 10-day decitabine with venetoclax; ECOG PS, Eastern Cooperative Oncology Group performance status; ELN, European LeukemiaNet; HMA, hypomethylating agent; IC, intensive chemotherapy; allo-SCT, allogeneic stem cell transplantation. |
|||
Characteristic, % unless otherwise stated |
DEC10-VEN |
IC |
p value |
---|---|---|---|
Age, <60 years |
40 |
57 |
0.038 |
Sex, male |
60 |
55 |
0.539 |
AML type |
|||
Primary refractory |
43 |
42 |
— |
Relapsed |
57 |
58 |
0.837 |
Secondary AML from AHD |
17 |
16 |
0.891 |
ECOG PS |
|||
0–1 |
71 |
73 |
0.734 |
≥2 |
29 |
27 |
— |
Median bone marrow blasts (range) |
34 (1–96) |
35 (0–98) |
0.536 |
ELN 2017 cytogenetic |
|||
Favorable |
0 |
0 |
— |
Intermediate |
63 |
62 |
0.958 |
Adverse |
37 |
38 |
— |
Mutations |
|||
NPM1 |
22 |
12 |
0.605 |
FLT3-ITD/TKD |
25 |
26 |
— |
IDH1/2 |
17 |
22 |
— |
TP53 |
28 |
25 |
— |
RUNX1 |
18 |
17† |
— |
ASXL1 |
15 |
11† |
— |
ELN 2017 risk group |
|||
Favorable |
15 |
8 |
0.302 |
Intermediate |
18 |
23 |
— |
Adverse |
66 |
68 |
— |
Median no. of prior therapies (range) |
2 (1–8) |
2 (1–10) |
0.721 |
Prior therapies |
|||
HMA |
25 |
18 |
0.214 |
IC only |
48 |
41 |
— |
IC and HMA |
25 |
41 |
— |
allo-SCT |
28 |
28 |
— |
Table 2. Efficacy outcomes*
CR, complete remission; CRi, CR with incomplete hematologic recovery; DEC10-VEN, 10-day decitabine with venetoclax; HR, hazard ratio; IC, intensive chemotherapy; MLFS, morphologic leukemia-free state; MRD, minimal residual disease; OR, odds ratio; ORR, CR + CRi + MLFS. |
||||
Outcomes |
DEC10-VEN |
IC (n = 130) |
OR/HR |
p value† |
---|---|---|---|---|
ORR |
60 |
28 |
3.28 |
< 0.001 |
CR/CRi |
42 |
23 |
2.52 |
0.009 |
CR |
23 |
17 |
1.44 |
0.320 |
CRi |
19 |
6 |
3.56 |
0.012 |
MLFS |
15 |
5 |
3.33 |
0.020 |
MRD negativity |
28 |
13 |
2.48 |
0.017 |
Refractory |
35 |
55 |
0.46 |
0.011 |
Relapse |
51 |
47 |
0.75 |
0.630 |
30-day mortality |
8 |
12 |
0.58 |
0.322 |
60-day mortality |
12 |
27 |
0.40 |
0.029 |
This retrospective cohort study demonstrated that DEC10-VEN can achieve high ORR, rates of CR, CRi, MLFS, MRD negativity, and better OS, and EFS. DEC10-VEN, being a low-intensity regimen, has the potential to act as a bridge to SCT. Taken the findings together, DEC10-VEN may be an appropriate salvage option for venetoclax-naïve patients with R/R AML. Although, propensity score matching minimized any biases, the study was still limited by a small number of patients in the DEC10-VEN cohort for any exploratory subgroup analysis, time bias, and single-centered studies. Several on-going studies evaluating venetoclax with FLAG-IDA (NCT03214562), CPX-351 (NCT03629171), and CLIA (NCT02115295) have shown promising early results.
References
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