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Secondary acute myeloid leukemia (sAML) comprises a heterogenous group of diseases. It is most often derived from conditions such as myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPNs), though there is a significant population with therapy-related AML (t-AML) related to prior treatment for a hematological lymphoid malignancy. Patients with t-AML typically have poor outcomes due to the pretreatment received, and/or an older age at diagnosis. Allogeneic hematopoietic stem cell transplant (allo-HSCT) is potentially curative for these patients, though relapse remains an issue. The allo-HSCT outcomes of patients who developed a t-AML after treatment of a B-cell malignancy have not been well studied, and the potential impact of choice of conditioning regimens on post-transplant outcomes has not been discerned.
Katie S. Gatwood, Vanderbilt University Medical Center, Nashville, US, and colleagues conducted a multicenter, retrospective study using the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) registry. They aimed to evaluate the impact of myeloablative (MAC) versus reduced intensity conditioning (RIC) regimen on allo-HSCT outcomes in patients with t-AML following a lymphoid malignancy.
The authors analyzed data of adult patients with sAML (n= 549) who had previously been treated for a lymphoid malignancy and had received their first allo-HSCT between 2000–2016. The prior malignancies included acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), lymphoma and plasma cell dyscrasias. Patient characteristics at baseline are shown in Table 1.
Table 1. Baseline characteristics by conditioning regimenConditioning regimen
Myeloablative (MAC)
Reduced intensity (RIC)
N
258 (47%)
291 (53%)
Median age at transplant (years)
47.8
55.9
Median time from diagnosis to transplant (months)
4.7
4.7
Previous diagnosis:
· ALL
· CLL
· Lymphoma
· Multiple myeloma (MM)
· 25 (9.7%)
· 29 (11.2%)
· 194 (75.2%)
· 10 (3.9%)
· 15 (5.2%)
· 36 (12.4%)
· 219 (75.3%)
· 21 (7.2%)
AML cytogenetics
· Favorable
· Intermediate
· Adverse
· Missing
· 8 (3.1%)
· 73 (28.3%)
· 73 (28.3%)
· 104 (40.3%)
· 9 (3.1%)
· 96 (33%)
· 68 (23.4%)
· 118 (40.6%)
Disease status at allo-HSCT
· Active
· Complete remission (CR) 1
· CR2
· 80 (31%)
· 161 (62.4%)
· 17 (6.6%)
· 92 (31.6%)
· 181 (62.2%)
· 18 (6.2%)
Donor type
· Matched sibling (MSD)
· Unrelated (URD)
· Haploidentical
· Cord blood transplant
· 93 (36%)
· 126 (48.8%)
· 25 (9.7%)
· 14 (5.4%)
· 90 (30.9%)
· 174 (59.8%)
· 15 (5.2%)
· 12 (4.1%)
The efficacy results are shown in Table 2, by total cohort, and by conditioning regimen. Patients receiving RIC had a lower risk of non-relapse mortality (NRM), improved leukemia-free survival (LFS), and superior overall survival (OS, Table 3) in multivariate analysis. The choice of conditioning regimen did not significantly impact relapse incidence though.
Table 2. Efficacy results for the total cohort and by conditioning regimen and multivariate analysis
Total cohort, %
95% CI
MAC, %
95% CI
RIC, %
95% CI
p value
Two-year LFS
31.7
27.5–35.9
27.9
22–33.8
35.1
29.2–41
0.055
Two-year RI
39.1
34.8–43.4
38.6
32.3–44.9
39.6
33.7–45.5
0.82
Two-year OS
37.4
33–41.8
34.2
27.9–40.5
40.2
34.1–46.3
0.074
Two-year NRM
28.9
25–33
33.3
27.4–39.4
25.3
20.2–30.6
0.04
Two-year graft-versus-host disease (GvHD)-free relapse-free survival (GRFS)
22.8
19–26.6
19.8
14.5–25.1
25.5
20.1–30.9
0.148
Table 3. Factors significantly associated with outcomes in multivariate analysis
HR
95% CI
p value
LFS
Conditioning regimen (MAC vs RIC)
0.67
0.52–0.85
0.001
Prior autologous HSCT (yes)
1.3
1.01–1.67
0.04
Cytogenetics (adverse vs favorable)
3.15
1.35–7.37
0.008
Active disease at transplant vs CR1
1.68
1.31–2.56
< 0.001
CBT vs MSD
0.9
0.51–1.61
0.04
Donor (female to male)
1.35
1.03–1.77
0.028
OS
Conditioning regimen (MAC vs RIC)
0.69
0.53–0.89
0.004
Cytogenetics (intermediate vs favorable)
3.56
1.01–11.76
0.037
Cytogenetics (adverse vs favorable)
6.61
2–21.85
0.002
Active disease at transplant vs CR1
1.57
1.2–2.04
0.001
RI
Active disease at transplant vs CR1
2.25
1.62–3.13
< 0.001
Karnofsky performance status (KPS, < 80% vs ≥ 80%)
0.46
0.29–0.72
0.001
NRM
Conditioning (MAC vs RIC)
0.58
0.4–0.83
0.003
Cytogenetics (adverse vs favorable)
4.64
1.05–20.54
0.043
KPS (< 80% vs ≥ 80%)
0.4
0.24–0.66
< 0.001
Donor (female to male)
1.521
1.02–2.27
0.04
GFRS
Conditioning regimen (MAC vs RIC)
0.79
0.62–0.99
0.045
Cytogenetics (adverse vs favorable)
2.82
1.29–6.19
0.02
Active disease at transplant vs CR1
1.66
1.3–2.13
< 0.001
KPS (< 80% vs ≥ 80%)
0.47
0.34–0.66
< 0.001
Donor (female to male)
1.32
1.02–1.71
0.037
Rates of graft-versus-host disease (GvHD) are shown in Table 4. Unrelated donor transplant was associated with higher rate of grade II–IV aGvHD (HR: 1.67, 1.06–2.63, p= 0.027) and a KPS of > 80% was associated with lower rate of grade III–IV aGvHD (HR: 0.45, 0.2–1, p= 0.049).
Table 4. Cumulative incidence of GvHD for total cohort and by conditioning regimen
Total cohort, %, 95% CI
MAC, %, 95% CI
RIC, %, 95% CI
p value
Grade II–IV acute GvHD (aGvHD) at day 100 post-transplant
30.6
26.6–34.6
32.7
26.9–38.7
28.6
23.3–34.1
0.2
Grade III–IV aGvHD at day 100 post-transplant
13.7
10.9–16.8
15.37
11.1–20.1
12.3
8.7–16.5
0.26
Chronic GvHD (cGvHD) at two-years
27
23–31.1
23.7
18.3–29.6
30.1
24–36.4
0.16
Extensive cGvHD at two-years
12.8
9.9–16
11.4
7.5–16.1
14
10–18.6
0.38
Other variables associated with poor outcomes in the total cohort were; older age, adverse cytogenetics and active disease at time of transplant.
In total, 171 patients receiving MAC and 174 patients receiving RIC died. The main causes (> 10% of patients) were:
Given as MAC vs RIC
This study has some limitations, including the retrospective nature, potential for selection bias regarding intensity of conditioning, a lack of molecular characterization of AML subtype, a lack of analysis by disease risk, and missing cytogenetic data in around 40% of patients.
In summary, this analysis supports the use of allo-HSCT with RIC for patients with sAML following a prior lymphoid malignancy since patients treated with RIC regimens had a lower risk of NRM and improved LFS, OS and GFRS.
References