Minimal Residual Disease as a Predictive Factor for Relapse after Allogeneic Hematopoietic Stem Cell Transplant in Adult Patients with Acute Myeloid Leukemia in First and Second Complete Remission
Abstract
:1. Introduction
2. Experimental Section
2.1. MRD Assessment
2.2. Statistical Analyses
3. Results
Characteristics | Value | |||||
---|---|---|---|---|---|---|
CR1 | CR2 | Total (n/%) | ||||
MRD+ (n/%) | MRD− (n/%) | MRD+ (n/%) | MRD− (n/%) | |||
Patients (number, %) | 10 (100%) | 19 (100%) | 9 (100%) | 21 (100%) | 59 (100%) | |
Sex | ||||||
Male | 4 (40%) | 6 (31.6%) | 5 (55.5%) | 13 (90.5%) | 28 (47.5%) | |
Female | 6 (60%) | 13 (68.4%) | 4 (44.4%) | 8 (38.1%) | 31 (52.5%) | |
Age | ||||||
Range | 28–62 | 20–61 | 29–65 | 30–65 | 20–65 | |
Median | 51 | 44 | 48 | 43 | 48 | |
Mean | 51.0 | 42.4 | 49.0 | 46.3 | 46.3 | |
Initial cytogenetics | ||||||
Favorable | / | / | / | 1 (4.8%) | 1 (1.7%) | |
Intermediate | 4 (40%) | 7 (36.8%) | 5 (55.5%) | 17 (81%) | 33 (55.9%) | |
Unfavorable | 6 (60%) | 10 (52.6%) | 2 (22.2%) | 1 (4.8%) | 19 (32.2%) | |
Unknown | / | 2 (10.5%) | 2 (22.2%) | 2 (9.5%) | 6 (10.2%) | |
Diagnosis | ||||||
AML de novo | 4 (40%) | 13 (68.4%) | 7 (77.7%) | 17 (81%) | 41 (69.5%) | |
Secondary AML | 6 (60%) | 6 (31.6%) | 2 (22.2%) | 4 (19%) | 18 (30.5%) | |
Previous Stem Cell Transplant | 8 (13.6%) | |||||
Autologous | / | / | 3 (33.3%) | 4 (19%) | 7 (11.9%) | |
Allogeneic | / | / | / | 1 (4.8%) | 1 (1.7%) | |
Disease status at transplantation | ||||||
CR1 | 10 (100%) | 19 (100%) | / | / | 29 (49.1%) | |
CR2 | / | / | 9 (100%) | 21 (100%) | 30 (50.8%) | |
ECOG status | ||||||
0 | 3 (30%) | 10 (52.6%) | 1 (11.1%) | 4 (19%) | 18 (30.5%) | |
1 | 1 (10%) | 2 (10.5%) | 3 (33.3%) | 3 (14.3%) | 9 (15.2%) | |
2 | 1 (10%) | / | 1 (11.1%) | 3 (14.3%) | 5 (%) | |
3–4 | / | 1 (5.3%) | 1 (11.1%) | / | 2 (%) | |
unknown | 5 (50%) | 6 (31.6%) | 3 (33.3%) | 11 (52.4%) | 25 (%) | |
MRD defined by | ||||||
Flow cytometry | 3 (30%) | / | 6 (66.6%) | / | 9 (15.2%) | |
Cytogenetics | 4 (40%) | / | 4 (44.4%) | / | 8 (13.6%) | |
FISH | 5 (50%) | / | 2 (22.2%) | / | 7 (11.9%) | |
Leukemia cutis | / | / | 1 (11.1%) | / | 1 (1.7%) | |
Type of transplant | ||||||
Related | 6 (60%) | 10 (52.6%) | 6 (66.6%) | 12 (57.1%) | 34 (57.6%) | |
Unrelated | 4 (40%) | 9 (47.4%) | 3 (33.3%) | 9 (42.9%) | 25 (42.4%) | |
Graft type | ||||||
PBSC | 6 (60%) | 11 (57.9%) | 4 (44.4%) | 16 (76.2%) | 37 (62.7%) | |
Bone marrow | 1 (20%) | 3 (15.8%) | 3 (33.3%) | 3 (14.3%) | 10 (16.9%) | |
Cord blood | 3 (30%) | 5 (26.3%) | 2 (22.2%) | 2 (9.5%) | 12 (20.3%) | |
Donor-recipient HLA match | ||||||
Matched (8/8, 6/6) | 7 (70%) | 14 (73.7%) | 7 (77.7%) | 18 (85.7%) | 46 (78%) | |
Mismatched (7/8, 5/6) | 2 (20%) | 1 (5.3%) | 2 (22.2%) | 2 (9.5%) | 7 (11.9%) | |
Mismatched (4/6) | 1 (10%) | 4 (21%) | / | 1 (4.8%) | 6 (10.2%) | |
Condition intensity | ||||||
Myeloablative | 9 (90%) | 19 (100%) | 7 (77.7%) | 17 (81%) | 52 (88.2%) | |
Reduced intensity | 1 (10%) | / | 2 (22.2%) | 4 (19%) | 7 (11.9%) | |
Conditioning protocol | ||||||
Non TBI | 5 (50%) | 11 (57.9%) | 4 (44.4%) | 12 (57.2%) | 32 (54.3%) | |
TBI | 5 (50%) | 8 (42.1%) | 5 (55.5%) | 9 (42.9%) | 27 (45.7%) | |
Relapse | ||||||
Yes | 5 (50%) | 2 (10.5%) | 6 (66.6%) | 4 (19%) | 17 (28.8%) | |
No | 5 (50%) | 17 (89.5%) | 3 (33.3%) | 17 (81%) | 42 (71.2%) | |
Present status | ||||||
Alive | 2 (20%) | 12 (63.2%) | 2 (22.2%) | 11 (52.4%) | 27 (45.7%) | |
Diseased | 8 (80%) | 7 (36.8%) | 7 (77.7%) | 10 (47.6%) | 32 (54.3%) |
Pt.# | Age | Cytogenetics (initial) | Dg. | Prior SCT | Rem. status | Flow cytometry | Cytogenetics | FISH | Type of transplant | Conditioning protocol/intensity | Relapse | aGVHD | cGVHD | TRM | Cause of death | OS |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
10 | 61 | Normal | AML | No | CR1 | 2–3% myeloblasts | ck | / | R 8/8 PBSC | NonTBI/Reduced intensity | +85 | 0 | Yes | No | L, G, OF | +138 |
11 | 62 | 46, xy, del(7)(p15)[23]/47,xy,+8[7] | sAML | No | CR1 | 1% coexpressing CD34+/CD117+mb | 47, xy,+8 | Abn. signal pattern, +8 | R 8/8 PBSC | TBI/Myeloablative | +102 | 4 | No | No | L | +196 |
12 | 45 | normal | AML | No | CR2 | 3.5% abn mb | 46, xx | Normal signal pattern | R 8/8 PBSC | TBI/Myeloablative | +210 | 1 | Yes | No | L, G | +299 |
14 | 48 | normal; FISHdel16p13 | AML | Auto SCT | CR2 | 4% myeloblasts | 46, xy, del16 (q23,q23) | Abn. signal pattern, del 16p | R 8/8 PBSC | NonTBI/Myeloablative | +88 | 4 | No | No | L, G | +96 |
21 | 43 | normal | AML | No | CR2 | 2% mb, 25–30% monocytes | 46, xy | / | R 8/8 PBSC | NonTBI/Reduced intensity | +245 | 1 | No | No | L | +370 |
22 | 50 | normal | AML | No | CR1 | 15–20% monocytes | 46, xy | / | R 8/8 PBSC | TBI/Myeloablative | No | 1 | No | +82 | I | +82 |
25 | 49 | normal | AML | Auto SCT | CR2 | <2% myeloblasts | ck | / | U 6/6 CB | NonTBI/Myeloablative | No | 0 | No | Alive | Alive | >+1512 |
28 | 46 | t(11q23, 17q25)/t(11,17) | sAML | No | CR1 | 1% myeloblasts | 46, xx | MLL gene rearrangement 11q23 | R 8/8 BM | TBI/Myeloablative | +260 | 3 | No | Alive | Alive | >+370 |
31 | 29 | unknown | AML | No | CR2 | 1% abn mb | 46, xy | / | R 8/8 PBSC | NonTBI/Myeloablative | +42 | 0 | No | No | L | +98 |
32 | 56 | ck | sAML | No | CR2 | / | ck | Abn. signal pattern, +9/del7q | R 8/8 BM | NonTBI/Reduced intensity | +110 | 1 | No | No | L | +126 |
35 | 61 | unknown | AML | Auto SCT | CR2 | 3% abn monocytic cells | 46, xx | / | U 7/8 BM | NonTBI/Reduced intensity | +179 | 2 | No | No | L | +184 |
39 | 45 | normal | AML | No | CR2 | 5% abn mb 10% CD34+/CD117+mb | 46, xx | / | U 5/6 CB | TBI/Myeloablative | No | 3 | No | Alive | Alive | >+1051 |
43 | 48 | ck | sAML | No | CR1 | 1% mb | ck | Abn. signal pattern 5q−, 7q− | U 4/6 CB | NonTBI/Myeloablative | +601 | 1 | No | No | L | +662 |
46 | 28 | del7q− | AML | No | CR1 | 10% CD34+/CD117+mb | 46, xx | Normal signal pattern | U 5/6CB | NonTBI/Reduced intensity | No | 0 | No | No | L | +269 |
50 | 41 | del5q,7q | sAML | No | CR1 | 4% abn.mb | / | / | U 8/8 PBSC | TBI/Myeloablative | +114 | 2 | No | No | L | +156 |
52 | 61 | normal | sAML | No | CR1 | Leukemia cutis | 46, xy | / | R 8/8 PBSC | TBI/Myeloablative | No | 4 | No | +86 | H, G | +86 |
53 | 52 | 47, xx,+8 | AML | No | CR1 | <2% mb | 46, xx | Abn. signal pattern, +8q | U 5/6 CB | TBI/Myeloablative | No | 2 | No | Alive | Alive | >+638 |
54 | 61 | FISH del7q | sAML | No | CR1 | 4% mb | 46, xy,+1, der (1,7) (q10;p10) | Abn. signal pattern 7q, +21q | R 8/8 PBSC | TBI/Myeloablative | No | 4 | No | +78 | I, G, OF | +78 |
58 | 65 | del20q | sAML | No | CR2 | 4% abn. mb | 46, xy, del (20) (q11.2q13.3) | / | U 8/8 BM | NonTBI/Myeloablative | No | 0 | Yes | +385 | G, OF | +385 |
3.1. Overall Survival
3.2. Leukemia Free Survival
3.3. Relapse
3.4. Treatment-Related Mortality
MRD-negative | MRD-positive | ||||
(n = 40) | (67.8%) | (n = 19) | (32.2%) | ||
number | % | number | % | p-value | |
CR | |||||
1 | 19 | 47.5 | 10 | 52.6 | 0.7126 |
2 | 21 | 52.5 | 9 | 47.4 | |
Type/source of transplant | |||||
Related, PBSC | 22 | 55.0 | 9 | 47.4 | 0.0707 |
Related, BM | 0 | 0.0 | 3 | 15.8 | |
Unrelated, PBSC | 5 | 12.5 | 1 | 5.3 | |
Unrelated, BM | 6 | 15.0 | 1 | 5.3 | |
Unrelated, CB | 7 | 17.5 | 5 | 26.3 | |
HLA | |||||
Matched (8/8, 6/6) | 32 | 80.0 | 14 | 73.7 | 0.7282 |
Mismatched (7/8, 5/6) | 3 | 7.5 | 4 | 21.1 | |
Mismatched (4/6) | 5 | 12.5 | 1 | 5.3 | |
Initial cytogenetics | |||||
Favorable | 1 | 2.5 | 0 | 0.0 | 0.2145 |
Intermediate | 24 | 60.0 | 9 | 47.4 | |
Unfavorable | 11 | 27.5 | 8 | 42.1 | |
Unknown | 4 | 10.0 | 2 | 10.5 | |
Previous disease/HSCT | |||||
AML de novo | 27 | 67.5 | 8 | 42.1 | 0.1016 |
Secondary AML | 8 | 20.0 | 8 | 42.1 | |
Prior HSCT | 5 | 12.5 | 3 | 15.8 | |
Conditioning protocol | |||||
Non TBI | 23 | 57.5 | 9 | 47.4 | 0.4655 |
TBI | 17 | 42.5 | 10 | 52.6 | |
Conditioning intensity | |||||
Myeleoblative | 36 | 90.0 | 16 | 84.2 | 0.6702 |
Reduced intensity | 4 | 10.0 | 3 | 15.8 | |
Mean | SD | Mean | SD | ||
Age | 44.45 | 11.8 | 50.05 | 10.6 | 0.0836 |
Factor | Unadjusted | |||
---|---|---|---|---|
Hazard Ratio | HRLowerCL | HRUpperCL | p-value | |
MRD | 2.97 | 1.44 | 6.12 | 0.0032 |
CR: 2 vs. 1 | 1.08 | 0.54 | 2.17 | 0.8277 |
Initial cytogenetics | ||||
Unknown vs. favorable/intermediate | 0.97 | 0.28 | 3.35 | 0.9655 |
Unfavorable vs. favorable/intermediate | 1.78 | 0.85 | 3.72 | 0.1238 |
Previous disease/prior HSCT | ||||
Secondary vs. de novo AML | 1.52 | 0.71 | 3.22 | 0.2782 |
Previous SCT vs. de novo AML | 0.71 | 0.21 | 2.42 | 0.5813 |
Age (per year) | 1.03 | 1.00 | 1.07 | 0.0502 |
Transplant type, source and HLA | ||||
Type: unrelated vs. related | 0.49 | 0.23 | 1.04 | 0.0638 |
Source: CB vs. PBSC and BM | 0.19 | 0.04 | 0.79 | 0.0225 |
HLA: mismatched vs. matched | 0.27 | 0.08 | 0.89 | 0.0310 |
Conditioning protocol | ||||
TBI vs. non TBI | 0.83 | 0.41 | 1.67 | 0.5981 |
Conditioning intensity | ||||
Reduced intensity vs. myeloablative | 1.07 | 0.37 | 3.08 | 0.9018 |
4. Discussion
5. Conclusions
Conflict of Interest
References
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Share and Cite
Grubovikj, R.M.; Alavi, A.; Koppel, A.; Territo, M.; Schiller, G.J. Minimal Residual Disease as a Predictive Factor for Relapse after Allogeneic Hematopoietic Stem Cell Transplant in Adult Patients with Acute Myeloid Leukemia in First and Second Complete Remission. Cancers 2012, 4, 601-617. https://doi.org/10.3390/cancers4020601
Grubovikj RM, Alavi A, Koppel A, Territo M, Schiller GJ. Minimal Residual Disease as a Predictive Factor for Relapse after Allogeneic Hematopoietic Stem Cell Transplant in Adult Patients with Acute Myeloid Leukemia in First and Second Complete Remission. Cancers. 2012; 4(2):601-617. https://doi.org/10.3390/cancers4020601
Chicago/Turabian StyleGrubovikj, Rada M., Asif Alavi, Ahrin Koppel, Mary Territo, and Gary J. Schiller. 2012. "Minimal Residual Disease as a Predictive Factor for Relapse after Allogeneic Hematopoietic Stem Cell Transplant in Adult Patients with Acute Myeloid Leukemia in First and Second Complete Remission" Cancers 4, no. 2: 601-617. https://doi.org/10.3390/cancers4020601