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Reduced-intensity conditioning (RIC) regimens allow patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) who are unfit for myeloablative conditioning regimens to receive allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the prognostic impact of post-transplant T-cell chimerism and measurable residual disease (MRD) in patients with AML or MDS receiving RIC allo-HSCT has not been assessed prospectively.1
The AML Hub previously reported results from the randomized phase II FIGARO trial of patients receiving allo-HSCT for AML or MDS, comparing a fludarabine + cytarabine + amsacrine + busulfan + anti-thymocyte globulin (FLAMSA-Bu) RIC regimen with the investigator’s standard fludarabine-based RIC regimen choice.1 The Hub has also previously published a video interview with Charles Craddock discussing predictors of outcomes post-transplant from this trial. Recently, Loke et al.1 published further analyses from the trial in Blood Advances assessing the impact of post-transplant MRD and T-cell chimerism status on survival outcomes.
The study design of the FIGARO trial has been covered previously. Serial samples for MRD analysis, assessed by flow cytometry, were collected pre-transplant, and for 187 patients, post-transplant at Day 42, and Months 3, 6, 9, and 12. Peripheral blood samples for T-cell chimerism were collected every 3 months during the first year post-transplant. The median follow-up was 49.7 months.
Table 1. Baseline characteristics*
Characteristics, % unless otherwise specified |
Overall |
Post-transplant MRD status |
p value |
|
---|---|---|---|---|
Positive at any time point (n = 29) |
Negative only (n = 158) |
|||
RIC regimen |
|
|
|
|
FLAMSA-Bu |
50 |
34 |
49 |
0.21 |
Flu/Bu/ATG |
29 |
31 |
32 |
- |
Flu/melphalan/alemtuzumab |
14 |
21 |
13 |
- |
Flu/Bu/alemtuzumab |
7 |
14 |
6 |
- |
Age |
|
|
|
|
≤60 years |
58 |
66 |
59 |
0.61 |
>60 years |
42 |
34 |
41 |
- |
Sex |
|
|
|
|
Female |
42 |
38 |
43 |
0.97 |
Male |
58 |
62 |
57 |
- |
Underlying disease |
|
|
|
|
AML |
67 |
69 |
64 |
0.44 |
MDS |
33 |
31 |
36 |
- |
Patients with cytogenetic risk-AML |
|
|
|
|
Adverse risk |
31 |
45 |
23 |
0.11 |
Intermediate risk |
64 |
45 |
71 |
- |
Favorable risk |
5 |
10 |
5 |
- |
Unknown |
1 |
- |
1 |
- |
Disease status (AML only) |
|
|
|
|
CR1/CR2 |
96 |
90 |
97 |
0.38 |
Primary refractory |
4 |
10 |
3 |
- |
FLT3 |
|
|
|
|
Absent |
40 |
38 |
39 |
0.76 |
Present |
17 |
24 |
18 |
- |
NPM1 |
|
|
|
|
Absent |
41 |
52 |
39 |
0.90 |
Present |
16 |
10 |
18 |
- |
Donor type |
|
|
|
|
Sibling |
21 |
28 |
20 |
0.82 |
Unrelated |
79 |
72 |
80 |
- |
Pre-transplant MRD |
|
|
|
|
Positive |
20 |
34 |
20 |
0.03 |
Negative |
52 |
41 |
56 |
- |
Missing |
28 |
24 |
24 |
- |
AML, acute myeloid leukemia; ATG, anti-thymocyte globulin; Bu, busulfan; CR1/CR/2, first or second complete remission; FLAMSA, fludarabine + cytarabine + amsacrine; Flu, fludarabine; MDS, myelodysplastic syndromes; MRD, measurable residual disease; RIC, reduced-intensity conditioning. |
Table 2. 2-year estimated survival outcomes based on MRD status at each time point*
Outcome |
Time point |
Post-transplant MRD status |
||
---|---|---|---|---|
MRD+ 2-year estimate (95% CI) |
MRD− 2-year estimate (95% CI) |
p value |
||
CIR |
Day 42 |
92.3 (35.8–99.4) |
22.9 (16.4–30.1) |
<0.001 |
Month 3 |
50.0 (19.2–74.8) |
20.5 (14.0–27.7) |
0.011 |
|
Month 6 |
83.3 (8.6–98.7) |
17.4 (11.1–24.9) |
<0.001 |
|
Month 9 |
100 |
14.6 (8.5–22.1) |
<0.001 |
|
Month 12 |
50.0 (0.0–96.0) |
14.0 (8.0–21.6) |
0.19 |
|
OS |
Day 42 |
30.8 (9.5–55.4) |
66.9 (58.5–74.0) |
<0.001 |
Month 3 |
58.3 (27.0–80.1) |
74.0 (65.5–80.6) |
0.30 |
|
Month 6 |
50.0 (11.1–80.4) |
80.6 (72.0–86.8) |
<0.0001 |
|
Month 9 |
33.3 (0.9–77.4) |
87.8 (79.5–92.9) |
<0.0001 |
|
Month 12 |
50.0 (0.6–91.0) |
94.7 (87.8–97.8) |
0.18 |
|
RFS |
Day 42 |
7.7 (0.5–29.2) |
61.0 (52.6–68.5) |
<0.001 |
Month 3 |
50.0 (20.8–73.6) |
67.3 (58.6–74.6) |
0.13 |
|
Month 6 |
16.7 (0.8–51.7) |
75.4 (66.3–82.3) |
<0.001 |
|
Month 9 |
33.3 (0.9–77.4) |
79.3 (69.7–86.2) |
<0.001 |
|
Month 12 |
50.0 (0.6–91.0) |
83.7 (74.4–89.9) |
0.31 |
|
CI, confidence interval; CIR, cumulative incidence of relapse; MRD, measurable residual disease; OS, overall survival; RFS, relapse-free survival. |
T-cell chimerism and post-transplant MRD data up to Month 6 were available for 94 patients.
Figure 1. Impact of T-cell chimerism and post-transplant MRD status on estimated 2-year survival outcomes*
MRD, measurable residual disease; OS, overall survival; RFS, relapse-free survival.
*Data from Loke et al.1
It is thought that the graft-versus-leukemia effect of allo-HSCT may be affected by downregulation of HLA Class II molecules on the surfaces of leukemic blasts; therefore, the association of increased risk of relapse with MRD positivity and HLA-DR downregulation was investigated.
This analysis from the FIGARO trial demonstrated the prognostic significance of post-transplant MRD, independent of pre-transplant MRD status, in patients with AML or MDS who underwent allo-HSCT using a RIC regimen. This analysis also showed the impact of T-cell chimerism on transplant outcomes and the interaction with post-transplant MRD, and that HLA-DR blast expression can provide further prognostic information in patients who are MRD+ post-transplant.
The authors concluded that the results from this study support combined MRD and T-cell donor chimerism monitoring for patients with AML or MDS following RIC allo-HSCT.
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