Association of Genomic Alterations with the Presence of Serum Monoclonal Proteins in Chronic Lymphocytic Leukemia
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients
2.2. Serum Immunofixation Electrophoresis
2.3. Next-Generation Sequencing
2.4. Statistical Analysis
3. Results
3.1. Clinical and Laboratory Characteristics
3.2. Genomic Characteristics
3.3. Heavy-Chain Immunoglobulin Isotype
3.4. Light-Chain Immunoglobulin Isotype
3.5. Treatment and Survival
4. Discussion
Supplementary Materials
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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sIFE at the Time of NGS | ||||
---|---|---|---|---|
Characteristic | All Patients (n = 97) | Negative (n = 48, 49%) | Positive (n = 49, 51%) | p Value |
Age in years, median (range) | 69 (41–96) | 68 (44–96) | 70 (41–94) | NS |
Male sex, n (%) | 57 (59) | 27 (56) | 30 (61) | NS |
Diagnosis | ||||
CLL, n (%) | 89 (92) | 43 (90) | 46 (94) | NS |
MBL, n (%) | 5 (5) | 4 (8) | 1 (2) | |
SLL, n (%) | 3 (3) | 1 (2) | 2 (4) | |
ECOG PS ≥ 1, n (%) (n = 89) | 8 (9) | 2 (4) | 6 (14) | NS |
B symptoms, n (%) | 2 (2) | 0 | 2 (4) | NS |
Binet stage C, n (%) | 13 (13) | 5 (10) | 8 (16) | NS |
Rai stage III-IV, n (%) | 14 (14) | 5 (10) | 9 (18) | NS |
Lymphadenopathy (CT), n (%) | 35 (36) | 14 (30) | 21 (43) | NS |
ALC > 15 × 109/L, n (%) | 56 (58) | 27 (56) | 29 (59) | NS |
LDH above ULN, n (%) (n = 92) | 13 (14) | 7 (15) | 6 (13) | NS |
β2-microglobulin above ULN, n (%) (n = 91) | 52 (57) | 21 (47) | 31 (67) | NS |
Complex karyotype (n = 88) | 7 (8) | 2 (5) | 5 (11) | NS |
FISH, n (%) | ||||
Normal | 15 (16) | 8 (18) | 7 (15) | NS |
del(13)(q14.3) | 37 (40) | 22 (49) | 15 (32) | |
Trisomy 12 | 13 (14) | 5 (11) | 8 (17) | |
del(11)(q22.3) | 8 (9) | 2 (4) | 6 (13) | |
del(17)(p13.1) | 19 (21) | 8 (18) | 11 (23) | |
CLL-IPI, n (%) (n = 87) | ||||
Low | 20 (23) | 13 (32) | 7 (15) | |
Intermediate | 16 (18) | 10 (24) | 6 (13) | 0.055 |
High | 33 (38) | 13 (32) | 20 (44) | |
Very high | 18 (21) | 5 (12) | 13 (28) | |
Diagnosis period | ||||
2003–2007 | 3 (3) | 1 (2) | 2 (4) | |
2008–2012 | 13 (13) | 9 (19) | 4 (8) | NS |
2013–2017 | 19 (20) | 10 (21) | 9 (19) | |
2018–2023 | 62 (64) | 28 (58) | 34 (69) | |
NGS and sIFE date | ||||
2003–2007 | 0 | 0 | 0 | |
2008–2012 | 3 (3) | 3 (6) | 0 | NS |
2013–2017 | 14 (14) | 7 (15) | 7 (14) | |
2018–2023 | 80 (83) | 38 (79) | 42 (86) |
sIFE at the Time of NGS | ||||
---|---|---|---|---|
Pathogenic/Likely Pathogenic Mutation | All Patients (n = 97) | Negative (n = 48, 49%) | Positive (n = 49, 51%) | p Value |
Presence of any mutation, n (%) | 51 (53) | 19 (40) | 32 (65) | 0.0196 |
Number of mutations, median (range) | 1 (0–4) | 0 (0–3) | 1 (0–4) | 0.0069 |
Number of mutated genes, median (range) | 1 (0–3) | 0 (0–2) | 1 (0–3) | 0.0061 |
ATM, n (%) | 9 (9) | 2 (4) | 7 (14) | NS |
BCL2, n (%) | 0 | 0 | 0 | - |
BIRC3, n (%) | 3 (5) | 2 (4) | 1 (2) | NS |
BTK, n (%) | 0 | 0 | 0 | - |
CXCR4, n (%) | 0 | 0 | 0 | - |
EGR2, n (%) | 1 (1) | 0 | 1 (2) | - |
FBXW7, n (%) | 8 (8) | 5 (10) | 3 (6) | NS |
KRAS, n (%) | 3 (3) | 0 | 3 (6) | NS |
MYD88, n (%) | 2 (2) | 0 | 2 (4) | NS |
NFKBIE, n (%) | 4 (4) | 0 | 4 (8) | NS |
NOTCH1, n (%) | 11 (11) | 3 (6) | 8 (16) | NS |
PLCG2, n (%) | 0 | 0 | 0 | - |
POT1, n (%) | 1 (1) | 0 | 1 (2) | - |
SF3B1, n (%) | 8 (8) | 3 (6) | 5 (10) | NS |
TP53, n (%) | 15 (15) | 7 (15) | 8 (16) | NS |
XPO1, n (%) | 6 (6) | 2 (4) | 4 (8) | NS |
Mutated Gene, n (%) | -sIFE/Non-IgG +sIFE (n = 69, 71%) | IgG +sIFE (n = 28, 29%) | p | -sIFE/Non-IgM +sIFE (n = 83, 86%) | IgM +sIFE (n = 14, 14%) | p | -sIFE/Monoclonal +sIFE (n = 85, 88%) | Bi/Triclonal (n = 12, 12%) | p |
---|---|---|---|---|---|---|---|---|---|
ATM | 4 (6) | 5 (18) | NS | 7 (8) | 2 (14) | NS | 6 (7) | 3 (25) | NS |
FBXW7 | 5 (7) | 3 (11) | NS | 8 (10) | 0 | NS | 7 (8) | 1 (8) | NS |
NFKBIE | 2 (3) | 2 (7) | NS | 4 (5) | 0 | NS | 3 (4) | 1 (8) | NS |
NOTCH1 | 6 (7) | 6 (21) | NS | 10 (12) | 2 (14) | NS | 8 (9) | 4 (33) | 0.04 |
SF3B1 | 3 (4) | 5 (18) | 0.04 | 7 (8) | 1 (7) | NS | 5 (6) | 3 (25) | NS |
TP53 | 11 (16) | 4 (14) | NS | 10 (12) | 5 (36) | 0.04 | 12 (14) | 3 (25) | NS |
XPO1 | 2 (3) | 4 (14) | NS | 5 (6) | 1 (7) | NS | 3 (4) | 3 (25) | 0.03 |
sIFE at the Time of NGS | ||||
---|---|---|---|---|
First Line of Treatment * | Patients (n = 76) | Negative (n = 40, 53%) | Positive (n = 36, 47%) | p Value |
Untreated, n (%) | 45 (60) | 24 (60) | 21 (58) | NS |
BTKi, n (%) | 29 (38) | 15 (37) | 14 (39) | |
Ibrutinib | 20 (70) | 11 (74) | 9 (65) | |
Acalabrutinib | 5 (17) | 2 (13) | 3 (21) | |
Zanubrutinib | 4 (13) | 2 (13) | 2 (14) | |
BCL2i, n (%) | 1 (1) | 0 | 1 (3) | |
Immunochemotherapy n (%) | 1 (1) | 1 (3) | 0 |
Univariable Analysis | Multivariable Analysis (75 Cases, 27 Events) | ||||
---|---|---|---|---|---|
Parameter | Risk Category | HR (95% CI) | p | HR (95% CI) | p Value |
Sex | Male | 0.72 (0.34–1.53) | NS | NI a | |
Age | >65 years | 1.44 (0.63–3.32) | NS | NI b | |
Stage | Binet B-C and/or Rai I-IV | 3.47 (1.39–8.68) | 0.008 | NI b | |
ECOG PS | ≥1 | 1.85 (0.47–7.27) | NS | NI a | |
ALC | >15 × 109/L | 1.02 (0.49–2.13) | NS | NI a | |
B2M levels | >3.5 mg/L | 3.13 (1.33–7.4) | 0.01 | NI b | |
IGHV status | Unmutated | 4.16 (1.69–10.25) | 0.001 | NI b | |
del(17p) and/or TP53 mutation | Present | 1.28 (0.56–2.9) | NS | NI b | |
CLL-IPI risk group | Intermediate/ High-risk | 2.98 (0.85–10.39) | NS | 2.68 (0.76–9.4) | NS |
Very high-risk | 6.28 (1.68–23.52) | 0.006 | 4.8 (1.32–18.71) | 0.02 | |
sIFE | Positive | 2.6 (1.14–6.08) | 0.03 | 1.86 (0.79–4.41) | NS |
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Piñeyroa, J.A.; López-Oreja, I.; Nadeu, F.; Martínez-Farran, A.; Aróstegui, J.I.; López-Guerra, M.; Correa, J.G.; Fabregat, A.; Villamor, N.; Monge-Escatín, I.; et al. Association of Genomic Alterations with the Presence of Serum Monoclonal Proteins in Chronic Lymphocytic Leukemia. Cells 2024, 13, 1839. https://doi.org/10.3390/cells13221839
Piñeyroa JA, López-Oreja I, Nadeu F, Martínez-Farran A, Aróstegui JI, López-Guerra M, Correa JG, Fabregat A, Villamor N, Monge-Escatín I, et al. Association of Genomic Alterations with the Presence of Serum Monoclonal Proteins in Chronic Lymphocytic Leukemia. Cells. 2024; 13(22):1839. https://doi.org/10.3390/cells13221839
Chicago/Turabian StylePiñeyroa, Juan A., Irene López-Oreja, Ferran Nadeu, Ares Martínez-Farran, Juan Ignacio Aróstegui, Mónica López-Guerra, Juan Gonzalo Correa, Aleix Fabregat, Neus Villamor, Ines Monge-Escatín, and et al. 2024. "Association of Genomic Alterations with the Presence of Serum Monoclonal Proteins in Chronic Lymphocytic Leukemia" Cells 13, no. 22: 1839. https://doi.org/10.3390/cells13221839
APA StylePiñeyroa, J. A., López-Oreja, I., Nadeu, F., Martínez-Farran, A., Aróstegui, J. I., López-Guerra, M., Correa, J. G., Fabregat, A., Villamor, N., Monge-Escatín, I., Albiol, N., Costa, D., Aymerich, M., Beà, S., Campo, E., Delgado, J., Colomer, D., & Mozas, P. (2024). Association of Genomic Alterations with the Presence of Serum Monoclonal Proteins in Chronic Lymphocytic Leukemia. Cells, 13(22), 1839. https://doi.org/10.3390/cells13221839