Background
Methods
Study design
Transplant protocol
Donor lymphocyte infusion
MFC detection of MRD
Outcome
Statistical analysis
Characteristics | All patients | MSDT | HBMT | ||||
---|---|---|---|---|---|---|---|
MRDneg | MRDpos | MRDneg | MRDpos | ||||
Number of patients | 339 | 85 | 14 | 189 | 51 | ||
Median age (range), years | 31 (2–60) | 41 (12–57) | 44 (5–57) | 0.457 | 27 (2–60) | 28 (9–57) | 0.151 |
Weight (range), kg | 61 (15.5–118) | 66.5 (29–97) | 68 (23–96) | 1.000 | 64 (15.5–118) | 60 (25–102) | 0.286 |
Male, n (%) | 165 (48.7%) | 41 (48.2%) | 9 (64.3%) | 0.263 | 96 (50.8%) | 19 (37.3%) | 0.086 |
Diagnosis, n (%) | 0.264 | 0.031 | |||||
De novo AML | 333 (98.2%) | 84 (98.8%) | 13 (92.9%) | 188 (99.5%) | 48 (94.1%) | ||
Secondary AML | 6 (1.8%) | 1 (1.2%) | 1 (7.1%) | 1 (0.5%) | 3 (5.9%) | ||
Disease status, n (%) | 0.217 | 0.137 | |||||
CR1 | 301 (88.8%) | 81 (95.3%) | 12 (85.7%) | 167 (88.4%) | 41 (80.4%) | ||
CR > 1 | 38 (11.2%) | 4 (4.7%) | 1 (14.3%) | 22 (11.6%) | 10 (19.6%) | ||
FLT3-ITD mutation | 0.302 | 0.582 | |||||
Yes | 20 (5.9%) | 5 (5.9%) | 2 (14.3%) | 11 (5.8%) | 2 (3.9%) | ||
No | 319 (94.1%) | 80 (94.1%) | 12 (85.7%) | 178 (94.2%) | 49 (96.1%) | ||
Cytogenetics | 0.247 | 0.285 | |||||
Favorable | 59 (17.4%) | 16 (18.8%) | 1 (7.1%) | 30 (15.9%) | 12 (23.5%) | ||
Intermediate | 263 (77.6%) | 65 (76.5%) | 13 (92.9%) | 150 (79.4%) | 35 (68.6%) | ||
Adverse | 17 (5.0%) | 4 (4.7%) | 0 | 9 (4.8%) | 4 (7.8%) | ||
Conditioning regimen, n (%) | |||||||
MA | 339 (100%) | 85 (100%) | 14 (100%) | 189 (100%) | 51 (100%) | ||
HLA-A-, B-, and DR-mismatched grafts, n (%) | 0.245 | ||||||
0 | 101 (29.8%) | 85 (100%) | 14 (100%) | 1 (0.5%) | 1 (2.0%) | ||
1 | 14 (4.1%) | 0 | 0 | 13 (6.9%) | 1 (2.0%) | ||
2 | 55 (16.2%) | 0 | 0 | 40 (21.2%) | 15 (29.4%) | ||
3 | 126 (49.9%) | 0 | 0 | 135 (71.4%) | 34 (66.7%) | ||
Donor-recipient sex-matched grafts, n (%) | 0.249 | 0.481 | |||||
Male–male | 104 (30.7%) | 22 (25.9%) | 4 (28.6%) | 62 (32.8%) | 16 (31.4%) | ||
Male–female | 86 (25.3%) | 25 (29.4%) | 1 (7.1%) | 55 (29.1%) | 14 (27.5%) | ||
Female–male | 95 (28.0%) | 32 (37.6%) | 8 (57.1%) | 44 (23.3%) | 8 (17.6%) | ||
Female–female | 47 (13.9%) | 6 (7.1%) | 1 (7.1%) | 28 (14.8%) | 12 (23.5%) | ||
Donor-recipient relationship, n (%) | 0.439 | ||||||
Parent–child | 128 (37.8%) | 0 | 0 | 104 (55.0%) | 24 (47.1%) | ||
Sibling–sibling | 176 (51.9%) | 85 (100%) | 14 (100%) | 58 (30.7%) | 19 (37.3%) | ||
Child–parent | 32 (9.4%) | 0 | 0 | 24 (12.7%) | 8 (15.7%) | ||
Other | 3 (0.9%) | 0 | 0 | 3 (1.6%) | 0 (0%) | ||
ABO matched grafts, n (%) | 0.087 | ||||||
Matched | 201 (59.3%) | 53 (62.4%) | 9 (64.3%) | 0.345 | 104 (55.0%) | 35 (68.6%) | |
Major mismatch | 62 (18.3%) | 19 (22.4%) | 1 (7.1%) | 39 (20.6%) | 3 (5.9%) | ||
Minor mismatch | 58 (17.1%) | 9 (10.6%) | 2 (14.3%) | 36 (19.0%) | 11 (21.6%) | ||
Bi-directional mismatch | 18 (5.3%) | 4 (4.7%) | 2 (14.3%) | 10 (5.3%) | 2 (3.9%) | ||
EBMT score, n (%) | 0.063 | 0.850 | |||||
0 | 0 | 0 | 0 | 0 | 0 | ||
1 | 73 (21.5%) | 23 (27.1%) | 3 (21.4%) | 38 (20.1%) | 9 (17.6%) | ||
2 | 156 (46.0%) | 50 (58.8%) | 7 (50.0%) | 78 (41.3%) | 21 (41.2%) | ||
3 | 76 (22.4%) | 11 (12.9%) | 1 (7.1%) | 50 (26.5%) | 14 (27.5%) | ||
4 | 25 (7.4%) | 1 (1.2%) | 2 (14.2%) | 18 (9.5%) | 4 (7.8%) | ||
5 | 9 (2.7%) | 0 | 1 (7.1%) | 5 (2.6%) | 3 (5.9%) | ||
Cell compositions in allografts | |||||||
Infused nuclear cells, (range) 108/kg | 7.51 (3.98–16.77) | 7.51 (3.98–14.75)(5.18–14.93) | 7.12 (5.78–12.75) | 0.896 | 7.40 (4.32–16.77) | 7.69 (5.4–14.07) | 0.262 |
Infused CD34+ cells, (range) 106/kg | 2.32 (0.50–9.78) | 2.26 (0.76–9.78) | 2.05 (1.16–5.04) | 0.670 | 2.32 (0.50–9.47) | 2.46 (1.04–8.80) | 0.448 |
DLI after transplant, n (%) | |||||||
For relapse prophylaxis and intervention | 28 (8.3%) | 6 (7.1%) | 4 (28.6%) | 0.046 | 13 (6.9%) | 5 (9.8%) | 0.686 |
For relapse treatment | 19 (5.6%) | 2 (2.4%) | 2 (14.3%) | 0.171 | 12 (6.3%) | 3 (5.9%) | 0.902 |
Results
Patient characteristics and transplant outcomes
Characteristics | All patients | MSDT | HBMT | ||||
---|---|---|---|---|---|---|---|
MRDneg | MRDpos | MRDneg | MRDpos | ||||
Number of patients | 340 | 62 | 20 | 202 | 56 | ||
Median age (range), years | 32 (3–65) | 39 (4–55) | 41.5 (7–62) | 0.612 | 30 (3–65) | 26 (4–61) | 0.151 |
Weight (range), kg | 62 (15.5–140) | 63 (15.5–91) | 65.25 (28–95) | 0.631 | 62 (17–140) | 58 (19–92) | 0.090 |
Male, n (%) | 208 (61.2%) | 32 (51.6%) | 15 (75.0%) | 0.066 | 127 (62.9%) | 34 (60.7%) | 0.768 |
Diagnosis, n (%) | 0.146 | 0.603 | |||||
De novo AML | 318 (93.5%) | 61 (98.4%) | 18 (90.0%) | 187 (92.6%) | 52 (92.9%) | ||
Secondary AML | 22 (6.5%) | 1 (1.6%) | 2 (10.0%) | 15 (7.4%) | 4 (7.1%) | ||
Disease status, n (%) | 0.165 | ||||||
CR1 | 293 (86.2%) | 56 (90.3%) | 15 (75.0%) | 0.080 | 177 (87.6%) | 45 (80.4%) | |
CR > 1 | 47 (13.8%) | 6 (9.7%) | 5 (25.0%) | 25 (12.4%) | 11 (19.6%) | ||
FLT3-ITD mutation | 0.390 | 0.610 | |||||
Yes | 49 (14.4%) | 11 (17.7%) | 2 (10.0%) | 27 (13.4%) | 9 (16.1%) | ||
No | 291 (85.6%) | 51 (82.3%) | 18 (90.0%) | 175 (86.6%) | 47 (83.9%) | ||
Cytogenetics | 0.500 | 0.277 | |||||
Favorable | 43 (12.6%) | 7 (11.3%) | 1 (5.0%) | 28 (13.9%) | 7 (12.5%) | ||
Intermediate | 263 (77.4%) | 50 (80.6%) | 16 (80.0%) | 157 (77.7%) | 40 (71.4%) | ||
Adverse | 34 (10.0%) | 5 (8.1%) | 3 (15.0%) | 17 (8.4%) | 9 (16.1%) | ||
Conditioning regimen, n (%) | |||||||
MA | 340 (100%) | 62 (100%) | 20 (100%) | 202 (100%) | 56 (100%) | ||
HLA-A-, B-, and DR-mismatched grafts, n (%) | 0.599 | ||||||
0 | 84 (24.7%) | 62 (100%) | 20 (100%) | 2 (1.0%) | 0 | ||
1 | 7 (2.1%) | 0 | 0 | 5 (2.5%) | 2 (3.6%) | ||
2 | 31 (9.1%) | 0 | 0 | 22 (10.9%) | 9 (16.1%) | ||
3 | 218 (64.1%) | 0 | 0 | 173 (85.6%) | 45 (80.4%) | ||
Donor-recipient sex-matched grafts, n (%) | |||||||
Male–male | 136 (40.0%) | 15 (24.2%) | 6 (30.0%) | 94 (46.5%) | 21 (37.5%) | ||
Male–female | 86 (25.3%) | 14 (22.6%) | 3 (15.0%) | 55 (27.2%) | 14 (25.0%) | ||
Female–male | 75 (22.1%) | 18 (29.0%) | 2 (10.0%) | 33 (16.3%) | 15 (26.8%) | ||
Female–female | 43 (12.6%) | 15 (24.2%) | 9 (45.0%) | 20 (9.9%) | 6 (10.7%) | ||
Donor-recipient relationship, n (%) | 0.283 | ||||||
Parent–child | 132 (38.8%) | 0 | 0 | 99 (49.0%) | 33 (58.9%) | ||
Sibling–sibling | 153 (45.0%) | 62 (100%) | 20 (100%) | 61 (30.2%) | 10 (17.9%) | ||
Child–parent | 49 (14.4%) | 0 | 0 | 37 (18.3%) | 12 (21.4%) | ||
Other | 6 (1.8%) | 0 | 0 | 5 (2.5%) | 1 (1.8%) | ||
ABO matched grafts, n (%) | 0.344 | ||||||
Matched | 179 (52.6%) | 40 (64.5%) | 14 (70.0%) | 0.660 | 97 (48.0%) | 28 (50.0%) | |
Major mismatch | 70 (20.6%) | 10 (16.1%) | 4 (20.0%) | 45 (22.3%) | 11 (19.6%) | ||
Minor mismatch | 72 (21.2%) | 8 (12.9%) | 2 (10.0%) | 46 (22.8%) | 16 (28.6%) | ||
Bi-directional mismatch | 19 (5.6%) | 4 (6.5%) | 0 | 14 (6.9%) | 1 (1.8%) | ||
EBMT score, n (%) | 0.125 | 0.546 | |||||
0 | 2 (0.6%) | 1 (1.6%) | 1 (5.0%) | 0 | 0 | ||
1 | 66 (19.4%) | 21 (33.9%) | 6 (30.0%) | 31 (15.3%) | 8 (14.3%) | ||
2 | 145 (42.6%) | 28 (45.2%) | 6 (30.0%) | 90 (44.6%) | 21 (37.5%) | ||
3 | 91 (26.8%) | 11 (17.7%) | 4 (20.0%) | 58 (28.7%) | 18 (32.1%) | ||
4 | 30 (8.8%) | 1 (1.6%) | 3 (15.0%) | 20 (9.9%) | 6 (10.7%) | ||
5 | 6 (1.8%) | 0 | 0 | 3 (1.5%) | 3 (5.4%) | ||
Cell compositions in allografts | |||||||
Infused nuclear cells, (range) 108/kg | 7.83 (2.27–16.66) | 7.59 (5.18–14.93) (5.18–14.93) | 7.22 (2.27–9.29) | 0.201 | 7.88 (3.93–15.97) | 8.17 (3.44–16.66) | 0.517 |
Infused CD34+ cells, (range) 106/kg | 2.55 (0.22–10.95) | 2.53 (0.41–6.43) | 2.65 (0.90–5.47) | 0.829 | 2.49 (0.22–10.95) | 2.78 (0.38–7.20) | 0.340 |
DLI after transplant, n (%) | |||||||
For relapse prophylaxis and intervention | 32 (9.4%) | 5 (8.1%) | 4 (20.0%) | 0.211 | 8 (4.0%) | 14 (25.0%) | <0.001 |
For relapse treatment | 8 (2.4%) | 2 (3.2%) | 2 (10.0%) | 0.249 | 3 (1.5%) | 2 (3.6%) | 0.297 |
Neutrophil engraftment | Platelet engraftment | Grades 2–4 acute GVHD | Chronic GVHD at 4 years | Relapse at 4 years | NRM at 4 years | LFS at 4 years | OS at 4 years | ||
---|---|---|---|---|---|---|---|---|---|
Retrospective study group (n = 339) | |||||||||
MSDT (n = 99) | MRDneg (group A) | 98% (95% CI, 96–100%) | 98% (95% CI, 94–100%) | 9% (95% CI, 3 to 15%) ‡, ##
| 58% (95% CI, 45 to 71%) | 11% (95% CI, 4 to 18%) | 16% (95% CI, 7 to 25%) | 73% (95% CI, 63 to 83%) | 76% (95% CI, 66 to 86%) |
MRDpos (group B) | 93% (95% CI, 79–100%) £
| 93% (95% CI, 79–100%) | 7% (95% CI, 0 to 21%) †, #
| 66% (95% CI, 35 to 97%) | 60% (95% CI, 22 to 98%) | 7% (95% CI, 0 to 21%) | 33% (95% CI, 2 to 64%) | 33% (95% CI, 2 to 64%) | |
Haplo-SCT (n = 240) | MRDneg (group C) | 99% (95% CI, 99–100%) | 99% (95% CI, 97–100%) | 36% (95% CI, 29 to 43%) | 48% (95% CI, 40 to 56%) | 15% (95% CI, 10 to 20%) | 14% (95% CI, 9 to 19%) | 71% (95% CI, 65 to 77%) | 75% (95% CI, 69 to 81%) |
MRDpos (group D) | 98% (95% CI, 96–100%) | 97% (95% CI, 93–100%) | 43% (95% CI, 29 to 57%) | 70% (95% CI, 56 to 84%) * | 19% (95% CI, 5 to 33%) | 8% (95% CI, 1 to 15%) | 73% (95% CI, 58 to 88%) | 75% (95% CI, 60 to 90%) | |
Prospective study group (n = 340) a
| |||||||||
MSDT (n = 82) | MRDneg (group E) | 98% (95% CI, 95–100%) | 98% (95% CI, 94–100%) | 10% (95% CI, 2 to 17%) $, $$
| 56% (95% CI, 39 to 72%) | 7% (95% CI, 0 to 13%) | 5% (95% CI, 0 to 11%) | 88% (95% CI, 79 to 97%) | 94% (95% CI, 87 to 100%) |
MRDpos (group F) | 95% (95% CI, 85–100%) ££
| 95% (95% CI, 85–100%) | 5% (95% CI, 0 to 15%) ††, ‡‡
| 41% (95% CI, 20 to 62%) | 36% (95% CI, 14 to 58%) | 16% (95% CI, 0 to 33%) | 48% (95% CI, 25 to 71%) | 64% (95% CI, 42 to 86%) | |
Haplo-SCT (n = 258) | MRDneg (group G) | 99% (95% CI, 99–100%) | 99% (95% CI, 99–100%) | 28% (95% CI, 21 to 35%) | 40% (95% CI, 31 to 49%) | 7% (95% CI, 3 to 11%) | 18% (95% CI, 12 to 24%) | 75% (95% CI, 69 to 81%) | 78% (95% CI, 72 to 84%) |
MRDpos (group H) | 97% (95% CI, 91–100%) | 98% (95% CI, 94–100%) | 32% (95% CI, 20 to 44%) | 73% (95% CI, 52 to 94%) ** | 13% (95% CI, 4 to 22%) | 7% (95% CI, 0 to 14%) | 80% (95% CI, 69 to 91%) | 83% (95% CI, 73 to 93%) |
Impact of pre-MRD on outcomes in patients receiving haplo-SCT versus MSDT
Haplo-SCT achieved better outcomes than MSDT for patients with pre-MRD-positive AML
Covariate | Univariate analysis | Multivariate analysis | ||||
---|---|---|---|---|---|---|
HR | 95% CI |
P value | HR | 95% CI |
P value | |
Relapse | ||||||
Disease status (CR1 vs. CR > 1) | 4.736 | 2.113–10.617 | <0.001 | 5.852 | 2.569–13.652 | <0.001 |
Transplant modality | 0.318 | 0.142–0.712 | 0.005 | 0.360 | 0.159–0.813 | 0.014 |
Chronic GVHD (yes vs. no) | 0.834 | 0.712–0.977 | 0.024 | 0.793 | 0.669–0.939 | 0.007 |
FLT3-ITD (yes vs. no) | 2.710 | 0.914–8.041 | 0.072 | |||
Transplant-related mortality | ||||||
Recipient age | 1.051 | 0.998–1.108 | 0.061 | |||
Neutrophil engraftment | 1.213 | 1.019–1.445 | 0.030 | 1.213 | 1.019–1.445 | 0.030 |
Leukemia-free survival | ||||||
Disease status (CR1 vs. CR > 1) | 3.542 | 1.715–7.318 | 0.001 | 4.554 | 2.127–9.752 | <0.001 |
Transplant modality | 0.300 | 0.149–0.602 | 0.001 | 0.334 | 0.165–0.677 | 0.001 |
Chronic GVHD (yes vs. no) | 0.812 | 0.705–0.934 | 0.004 | 0.783 | 0.675–0.909 | 0.001 |
FLT3-ITD (yes vs. no) | 2.501 | 0.951–6.575 | 0.063 | |||
Overall survival | ||||||
Disease status (CR1 vs. CR > 1) | 2.634 | 1.171–5.923 | 0.019 | 2.269 | 1.002–5.137 | 0.049 |
Transplant modality | 0.309 | 0.143–0.670 | 0.003 | 0.340 | 0.155–0.743 | 0.007 |