MRD as Biomarker for Response to Donor Lymphocyte Infusion after Allogeneic Hematopoietic Cell Transplantation in Patients with AML
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Patients and Treatment
2.2. Cytogenetic and Molecular Analysis
2.3. Error-Corrected Sequencing of Patient-Specific Mutations
2.4. Bioinformatics and Statistical Analyses
3. Results
3.1. Patient and Treatment Characteristics
3.2. Impact of Mutations and Baseline Characteristics at Diagnosis on Outcome of Patients Receiving DLIs
3.3. Remission and MRD Status at the Time of First DLI and Its Associations
3.4. MRD Conversion Day 30 and Day 90 after DLIs
3.5. Prognostic Effect of Remission and MRD Status at the Time of First DLI
3.6. Prognostic Effect of MRD Status in CR/CRi Patients 30 and 90 Days after DLI
3.7. Impact of DLIs on MRD− Patients
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Characteristic | All (n = 76) | CR/CRi MRD− (n = 23) | CR/CRi MRD+ (n = 15) | no CR/CRi at DLI (n = 38) | p | p (MRD− vs. MRD+) |
---|---|---|---|---|---|---|
Age at diagnosis | 0.19 | 0.73 | ||||
Median (years) | 52.9 | 50.7 | 52.8 | 55.9 | ||
Range (years) | 17.4–67.5 | 18.3–67.5 | 30–66.9 | 17.4–66 | ||
Patient sex | 0.049 | 0.013 | ||||
Male—no. (%) | 42 (55) | 9 (39) | 12 (80) | 21 (55) | ||
Female—no. (%) | 34 (45) | 14 (61) | 3 (20) | 17 (45) | ||
Diagnosis | 0.69 | 0.46 | ||||
De novo AML—no. (%) | 44 (58) | 15 (65) | 8 (53) | 21 (55) | ||
sAML/tAML/MDS/AML—no. (%) | 32 (42) | 8 (35) | 7 (47) | 17 (45) | ||
Extramedullary manifestation at diagnosis | 0.74 | 0.82 | ||||
Yes—no. (%) | 8 (11) | 2 (9) | 1 (7) | 5 (13) | ||
No—no. (%) | 68 (89) | 21 (91) | 14 (93) | 33 (87) | ||
FAB subtype | 0.51 | 0.34 | ||||
M0 + M1 + M2—no. (%) | 29 (38) | 11 (48) | 5 (33.3) | 13 (34) | ||
M4 + M5 + M6 + M7—no. (%) | 22 (29) | 5 (22) | 5 (33.3) | 12 (32) | ||
Not classifiable—no. (%) | 25 (33) | 7 (30) | 5 (33.3) | 13 (34) | ||
FLT3-ITD status at diagnosis | 0.4 | 0.23 | ||||
Mutated—no. (%) | 16 (21) | 7 (30) | 2 (13) | 7 (18) | ||
Wild type—no. (%) | 59 (78) | 16 (70) | 13 (87) | 30 (79) | ||
Missing—no. (%) | 1 (1) | 0 (0) | 0 (0) | 1 (3) | ||
FLT3-TKD status at diagnosis | 0.2 | 0.07 | ||||
Mutated—no. (%) | 4 (5) | 0 (0) | 2 (13) | 2 (5) | ||
Wild type—no. (%) | 72 (95) | 23 (100) | 13 (87) | 36 (95) | ||
Complex karyotype | 0.96 | 0.98 | ||||
Yes—no. (%) | 11 (15) | 3 (13) | 2 (13) | 6 (16) | ||
No—no. (%) | 64 (84) | 19 (83) | 13 (87) | 32 (84) | ||
Missing—no. (%) | 1 (1) | 1 (4) | 0 (0) | 0 (0) | ||
Monosomal karyotype | 0.66 | 0.61 | ||||
Yes—no. (%) | 10 (13) | 3 (13) | 3 (20) | 4 (11) | ||
No—no. (%) | 65 (86) | 19 (83) | 12 (80) | 34 (89) | ||
Missing—no. (%) | 1 (1) | 1 (4) | 0 (0) | 0 (0) | ||
2022 ELN risk group | 0.77 | 0.85 | ||||
Favorable + Intermediate—no. (%) | 31 (41) | 10 (43) | 7 (47) | 14 (37) | ||
Adverse—no. (%) | 45 (59) | 13 (57) | 8 (53) | 24 (63) | ||
MRC Grimwade | 0.73 | 0.48 | ||||
Favorable + Intermediate—no. (%) | 56 (74) | 17 (74) | 10 (67) | 29 (76) | ||
Adverse—no. (%) | 19 (25) | 5 (22) | 5 (33) | 9 (24) | ||
Missing—no. (%) | 1 (1) | 1 (4) | 0 (0) | 0 (0) | ||
ECOG performance status at diagnosis | 0.67 | 0.75 | ||||
ECOG 0—no. (%) | 70 (92) | 22 (96) | 14 (93) | 34 (89) | ||
ECOG 1—no. (%) | 6(8) | 1 (4) | 1 (7) | 4 (11) | ||
HCT–CI at diagnosis | 0.86 | 0.65 | ||||
0–2—no. (%) | 67 (88) | 21 (91) | 13 (87) | 33 (87) | ||
>2—no. (%) | 9 (12) | 2 (99 | 2 (13) | 5 (13) | ||
WBC count at diagnosis | 0.29 | 0.4 | ||||
Median—(×109/L) | 8 | 23.9 | 2.5 | 8.7 | ||
Range—(×109/L) | 0.9–115.2 | 1.2–115.2 | 1.4–106.8 | 0.9–70.6 | ||
Missing—no. (%) | 26 (34) | 6 (26) | 3 (20) | 17 (45) | ||
Hemoglobin at diagnosis | 0.78 | 0.43 | ||||
Median—g/dL | 9.8 | 9.8 | 9.6 | 10.7 | ||
Range—g/dL | 5–15 | 5–14.4 | 7.9–12.3 | 5.2–15 | ||
Missing—no. (%) | 26 (34) | 6 (26) | 3 (20) | 17 (45) | ||
Platelet count at diagnosis | 0.77 | 0.93 | ||||
Median—(×109/L) | 61 | 53.5 | 50.5 | 73 | ||
Range—(×109/L) | 7–1104 | 7–212 | 23–1104 | 14–469 | ||
Missing—no. (%) | 27 (36) | 7 (30) | 3 (20) | 17 (45) | ||
Blasts in PB at diagnosis | 0.15 | 0.45 | ||||
Median—% | 19.4 | 67 | 19.5 | 11 | ||
Range—% | 0–93 | 0–93 | 0–82 | 0–86 | ||
Missing—no. (%) | 29 (38) | 8 (35) | 3 (20) | 18 (47) | ||
Blasts in BM at diagnosis | 0.92 | 0.9 | ||||
Median—% | 48.4 | 40 | 46.7 | 50 | ||
Range—% | 5–95 | 20–95 | 20–95 | 5–90 | ||
Missing—no. (%) | 44 (58) | 15 (65) | 6 (40) | 23 (61) |
Univariate Analysis Results | Multivariate Analysis Results | ||||||
---|---|---|---|---|---|---|---|
Endpoint, Cohort | Variables in the Model | HR | 95% CI | p | HR | 95% CI | p |
EFS, n = 76 Before DLI | Extramedullary manifestation at diagnosis, yes vs. no | 2.48 | 1.11–5.57 | 0.028 | 2.41 | 1.06–5.49 | 0.036 |
MRC Grimwade, adverse vs. favorable + intermediate | 2.06 | 1.12–3.77 | 0.020 | 1.88 | 1.02–3.47 | 0.044 | |
No response or CR/CRi MRD+ vs. CR/CRi MRD− | 4.67 | 2.16–10.7 | <0.001 | 5.05 | 2.22–11.48 | <0.001 | |
OS, n = 76 Before DLI | Extramedullary manifestation at diagnosis, yes vs. no | 2.89 | 1.28–6.56 | 0.011 | 3.15 | 1.35–7.36 | 0.008 |
Complex karyotype, yes vs. no | 2.35 | 1.27–4.36 | 0.007 | 2.34 | 1.25–4.35 | 0.007 | |
No response or CR/CRi MRD+ vs. CR/CRi MRD− | 4.67 | 2.16–10.07 | <0.001 | 5.33 | 2.23–12.76 | <0.001 | |
CIR, n = 34 CR/CRi FU30 | Complex karyotype, yes vs. no | 3.43 | 0.87–13.56 | 0.078 | 6.72 | 1.35–33.41 | 0.02 |
FU30 MRD+ vs. MRD− | 2.64 | 0.86–8.13 | 0.09 | 4.6 | 1.21–17.5 | 0.025 | |
NRM, n = 34 CR/CRi FU30 | Pre DLI median age, ≤54 vs. >54 | 3.78 | 0.76–18.91 | 0.105 | 7.33 | 1.05–51.17 | 0.045 |
Extramedullary manifestation at diagnosis, yes vs. no | 5.21 | 0.89–30.41 | 0.066 | 13.02 | 3.32–51.13 | <0.001 | |
RFS, n = 34 CR/CRi FU30 | Complex karyotype, yes vs. no | 3.47 | 1.08–11.16 | 0.037 | 4.45 | 1.25–15.8 | 0.021 |
CMV status alloHCT1 | 2.57 | 0.84–7.87 | 0.098 | 3.27 | 1.0–10.67 | 0.049 | |
FU30 MRD+ vs. MRD | 2 | 0.77–5.17 | 0.154 | 3.91 | 1.31–11.65 | 0.015 | |
OS, n = 34 CR/CRi FU30 | Extramedullary manifestation at diagnosis, yes vs. no | 5.1 | 1.39–18.67 | 0.014 | 22.69 | 3.77–136.46 | 0.001 |
MRC Grimwade, adverse vs. favorable + intermediate | 2.87 | 1.00–8.26 | 0.05 | 4.56 | 1.36–15.34 | 0.014 | |
CMV status alloHCT1 | 3.19 | 0.90–11.29 | 0.072 | 6.13 | 1.34–28.06 | 0.019 | |
CIR, n = 37 CR/CRi FU90 | MRC Grimwade, adverse vs. favorable + intermediate | 2.68 | 0.84–8.53 | 0.095 | 4.02 | 1.14–14.22 | 0.031 |
FU90 MRD+ vs. MRD− | 3.02 | 1.02–8.94 | 0.047 | 4.66 | 1.42–15.31 | 0.011 | |
NRM, n = 37 CR/CRi FU90 | Pre DLI median age, ≤54 vs. >54 | 5.79 | 1.24–27.10 | 0.026 | 8.4 | 1.6–44.04 | 0.012 |
Extramedullary manifestation at diagnosis, yes vs. no | 4.78 | 1.10–20.87 | 0.037 | 8.71 | 3.22–23.57 | <0.001 | |
RFS, n = 37 CR/CRi FU90 | Extramedullary manifestation at diagnosis, yes vs. no | 3.59 | 1.19–10.86 | 0.024 | 7.36 | 1.38–39.1 | 0.019 |
Complex karyotype, yes vs. no | 3.17 | 1.02–9.90 | 0.047 | 6.79 | 1.86–24.81 | 0.004 | |
FU90 MRD+ vs. MRD | 2.27 | 0.87–5.92 | 0.095 | 4.53 | 1.93–10.66 | 0.001 | |
OS, n = 37 CR/CRi FU90 | Extramedullary manifestation at diagnosis, yes vs. no | 3.91 | 1.27–12.03 | 0.017 | 9.67 | 2.54–36.79 | 0.001 |
MRC Grimwade, adverse vs. favorable + intermediate | 2.64 | 1.02–6.82 | 0.045 | 4.27 | 1.46–12.48 | 0.008 | |
CMV status alloHCT1, other vs. D + P neg. | 3.01 | 0.99–9.11 | 0.052 | 4.26 | 1.29–14.07 | 0.017 |
Remission + MRD Status pre-DLI | n = 76 | Remission and MRD Status FU30 | Remission and MRD Status FU90 | ||
---|---|---|---|---|---|
CR/CRi MRD− | 23 (30%) | CR/CRi MRD− | 15 (65%) | CR/CRi MRD− | 12 (52%) |
CR/CRi MRD+ | 0 (0%) | CR/CRi MRD+ | 1 (4.5%) | ||
MRD not assessable | 8 (35%) | MRD not assessable | 9 (39%) | ||
No CR/CRi | 0 (0%) | No CR/CRi | 1 (4.5%) | ||
CR/CRi MRD+ | 15 (20%) | CR/CRi MRD− | 6 (40%) | CR/CRi MRD− | 11 (73.3%) |
CR/CRi MRD+ | 7 (47%) | CR/CRi MRD+ | 2 (13.3%) | ||
MRD not assessable | 0 (0%) | MRD not assessable | 0 (0) | ||
No CR/CRi | 2 (13%) | No CR/CRi | 2 (13.3%) | ||
Non-CR/CRi | 38 (50%) | CR/CRi MRD− | 4 (11%) | CR/CRi MRD− | 8 (21%) |
CR/CRi MRD+ | 2 (5%) | CR/CRi MRD+ | 3 (8%) | ||
CR/CRi MRD not assessed | 0 (0%) | CR/CRi MRD not assessed | 1 (3%) | ||
No CR/CRi | 32 (84%) | No CR/CRi | 26 (68%) |
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Teich, K.; Stadler, M.; Gabdoulline, R.; Kandarp, J.; Wienecke, C.; Heida, B.; Klement, P.; Büttner, K.; Venturini, L.; Wichmann, M.; et al. MRD as Biomarker for Response to Donor Lymphocyte Infusion after Allogeneic Hematopoietic Cell Transplantation in Patients with AML. Cancers 2023, 15, 3911. https://doi.org/10.3390/cancers15153911
Teich K, Stadler M, Gabdoulline R, Kandarp J, Wienecke C, Heida B, Klement P, Büttner K, Venturini L, Wichmann M, et al. MRD as Biomarker for Response to Donor Lymphocyte Infusion after Allogeneic Hematopoietic Cell Transplantation in Patients with AML. Cancers. 2023; 15(15):3911. https://doi.org/10.3390/cancers15153911
Chicago/Turabian StyleTeich, Katrin, Michael Stadler, Razif Gabdoulline, Jyoti Kandarp, Clara Wienecke, Bennet Heida, Piroska Klement, Konstantin Büttner, Letizia Venturini, Martin Wichmann, and et al. 2023. "MRD as Biomarker for Response to Donor Lymphocyte Infusion after Allogeneic Hematopoietic Cell Transplantation in Patients with AML" Cancers 15, no. 15: 3911. https://doi.org/10.3390/cancers15153911