Cumulative Dosage of Intrathecal Chemotherapy Agents Predicts White Matter Integrity in Long-Term Survivors of Acute Lymphoblastic Leukemia: A PETALE Study
Abstract
:Simple Summary
Abstract
1. Introduction
2. Methods
2.1. Study Design and Recruitment
2.2. Data Collection and Study Procedures
2.2.1. Neuroimaging Protocol
2.2.2. Neuroimaging Postprocessing
2.2.3. Magnetization Transfer Processing
2.2.4. Cognitive Assessment
2.3. Statistical Analysis
3. Results
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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ALL Survivors (n = 35) | Controls (n = 21) | p | |
---|---|---|---|
Demographics | |||
Sex, n (%) | |||
Male | 21 (60) | 12 (57.1) | 1.00 c |
Female | 14 (40) | 9 (42.9) | |
Age at assessment | 26.27 (6.39) | 27.1 (4.7) | 0.620 d |
Years of education | 12.63 (2.18) | 15.00 [11.00–18.00] b | 0.080 e |
Treatment characteristics | |||
Age at diagnosis a | 7.37 (5.55) | N/A | - |
DFCI protocol, n (%) | |||
87-01 | 5 (14.3) | N/A | - |
91-01 | 11 (31.4) | N/A | - |
95-01 | 13 (37.1) | N/A | - |
00-01 | 3 (8.6) | N/A | - |
05-01 | 3 (8.6) | N/A | - |
Cranial radiation therapy, n (%) | |||
Yes * | 27 (71.1) | N/A | - |
No | 8 (22.9) | N/A | - |
Chemotherapy cumulative doses | |||
IT methotrexate (MTX) (mg/m2) | 134.35 (54.42) a | N/A | - |
IT cytarabine (mg/m2) | 513.11 (197.65) a | N/A | - |
IT hydrocortisone (mg/m2) | 22.39 [8.20–268.67] b | N/A | - |
IV methotrexate (MTX) (mg/m2) | 6042.06 [1777.47–12,750.46] b | N/A | - |
Effective corticosteroids dose (g/m2) | 12,399.69 (5079.56) a | N/A |
ALLs (n = 35) | Controls (n = 21) | p | FDR adj.-p | Effect Size r | |
---|---|---|---|---|---|
WAIS-IV scales | |||||
FSIQ | 94.14 (14.35) a | 104.9 (13.7) a | 0.008 c | 0.022 | 0.35 |
GAI | 99.66 (11.81) a | 108.5 (13.5) a | 0.013 c | 0.024 | 0.33 |
VCI | 98.23 (11.64) a | 111 (83–123) b | 0.008 d | 0.022 | 0.35 |
PRI | 101.20 (14.57) a | 107.2 (13.8) a | 0.132 c | 0.182 | 0.20 |
WMI | 94.40 (13.54) a | 94 (76–137) b | 0.623 d | 0.623 | 0.07 |
PSI | 90.42 (20.63) a | 104.4 (12.7) a | 0.003 c | 0.022 | 0.39 |
DIVERGT scales | |||||
Executive Functioning Index | 8.70 (2.50) a | 10.10 (1.50) a | 0.012 c | 0.024 | 0.33 |
Digit span | 7.00 [3.00–14.00] b | 8.86 (2.39) a | 0.465 d | 0.512 | 0.10 |
Verbal fluency condition 1 | 7.91 (3.02) a | 8.86 (2.74) a | 0.248 c | 0.303 | 0.16 |
Trail making test condition 4 | 10.00 [1.00–15.00] b | 11.00 [8.00–14.00] b | 0.016 d | 0.022 | 0.31 |
Grooved pegboard dominant hand | 8.74 (3.36) a | 11.24 (2.59) a | 0.005 c | 0.022 | 0.37 |
FSIQ | GAI | VCI | PRI | WMI | PSI | EF Index | |
---|---|---|---|---|---|---|---|
IT-MTX dose | −0.391 * p = 0.010 padj = 0.033 | −0.387 * p = 0.011 padj = 0.027 | −0.104 p = 0.276 padj = 0.380 | −0.501 ** p = 0.001 padj = 0.005 | −0.295 * p = 0.043 padj = 0.215 | −0.250 p = 0.080 padj = 0.183 | −0.305 * p = 0.037 padj = 0.125 |
IT-cytarabine dose | −0.375 * p = 0.013 padj = 0.033 | −0.397 ** p = 0.009 padj = 0.027 | −0.131 p = 0.226 padj = 0.380 | −0.486 ** p = 0.002 padj = 0.005 | −0.221 p = 0.101 padj = 0.253 | −0.276 p = 0.060 padj = 0.183 | −0.282 p = 0.050 padj = 0.125 |
IT-hydrocortisone dose | 0.130 p = 0.479 padj = 0.479 | −0.150 p = 0.476 padj = 0.476 | −0.121 p = 0.311 padj = 0.380 | −0.183 p = 0.226 padj = 0.377 | −0.159 p = 0.258 padj = 0.323 | 0.134 p = 0.304 padj = 0.317 | 0.850 p = 0.365 padj = 0.426 |
IV-MTX dose | 0.091 p = 0.302 padj = 0.378 | 0.027 p = 0.440 padj = 0.476 | 0.054 p = 0.380 padj = 0.380 | −0.037 p = 0.417 padj = 0.417 | 0.153 p = 0.189 padj = 0.315 | 0.086 p = 0.317 padj = 0.317 | 0.033 p = 0.426 padj = 0.426 |
Effective corticosteroids dose | −0.156 p = 0.186 padj = 0.310 | −0.132 p = 0.225 padj = 0.375 | −0.153 p = 0.189 padj = 0.380 | −0.066 p = 0.353 padj = 0.417 | −0.025 p = 0.444 padj = 0.444 | −0.219 p = 0.110 padj = 0.183 | −0.169 p = 0.166 padj = 0.277 |
Effective Corticosteroids | IV MTX | IT MTX | IT Cytarabine | IT Hydrocortisone | |
---|---|---|---|---|---|
MTR means | |||||
Whole brain | 0.090 p = 0.303 padj = 0.379 | 0.020 p = 0.445 padj = 0.445 | −0.403 ** p = 0.008 padj = 0.015 | −0.405 ** p = 0.008 padj = 0.015 | −0.533 ** p = 0.009 padj = 0.015 |
Right hemisphere | 0.079 p = 0.326 padj = 0.408 | −0.034 p = 0.422 padj = 0.422 | −0.434 ** p = 0.005 padj = 0.013 | −0.437 ** p = 0.004 padj = 0.013 | −0.532 ** p = 0.009 padj = 0.015 |
Left hemisphere | 0.097 p = 0.290 padj = 0.301 | 0.091 p = 0.301 padj = 0.301 | −0.347 * p = 0.021 padj = 0.035 | −0.349 * p = 0.020 padj = 0.035 | −0.512 * p = 0.013 padj = 0.035 |
Corpus callosum (CC) | 0.009 p = 0.480 padj = 0.480 | 0.111 p = 0.263 padj = 0.329 | −0.283 * p = 0.050 padj = 0.083 | −0.284 * p = 0.049 padj = 0.083 | −0.398 * p = 0.046 padj = 0.083 |
Anterior CC | −0.045 p = 0.399 padj = 0.399 | 0.059 p = 0.369 padj = 0.399 | −0.351 * p = 0.019 padj = 0.048 | −0.359 * p = 0.017 padj = 0.048 | −0.405 * p = 0.043 padj = 0.072 |
Mid-anterior CC | 0.084 p = 0.316 padj = 0.395 | −0.011 p = 0.476 padj = 0.476 | −0.241 p = 0.081 padj = 0.135 | −0.241 p = 0.081 padj = 0.135 | −0.465 * p = 0.022 padj = 0.110 |
Central CC | 0.052 p = 0.384 padj = 0.499 | 0.256 p = 0.069 padj = 0.345 | −0.019 p = 0.457 padj = 0.499 | 0.000 p = 0.499 padj = 0.499 | −0.104 p = 0.336 padj = 0.499 |
Mid-posterior CC | −0.021 p = 0.453 padj = 0.453 | 0.196 p = 0.130 padj = 0.248 | −0.148 p = 0.198 padj = 0.248 | −0.148 p = 0.198 padj = 0.248 | −0.393 * p = 0.048 padj = 0.240 |
Posterior CC | 0.070 p = 0.345 padj = 0.411 | 0.039 p = 0.411 padj = 0.411 | −0.260 p = 0.066 padj = 0.123 | −0.250 p = 0.074 padj = 0.123 | −0.365 p = 0.062 padj = 0.123 |
Volumes | |||||
White matter (WM) | −0.178 p = 0.153 padj = 0.255 | 0.381 p = 0.012 padj = 0.060 | −0.097 p = 0.290 padj = 0.290 | −0.103 p = 0.278 padj = 0.290 | 0.227 p = 0.125 padj = 0.255 |
Intracranial volume | −0.298 * p = 0.041 padj = 0.068 | 0.358 p = 0.017 padj = 0.068 | −0.135 p = 0.219 padj = 0.219 | −0.142 p = 0.208 padj = 0.219 | 0.413 p = 0.039 padj = 0.068 |
WM volume fraction | 0.169 p = 0.166 padj = 0.345 | 0.157 p = 0.184 padj = 0.345 | 0.014 p = 0.469 padj = 0.495 | −0.002 p = 0.495 padj = 0.495 | −0.199 p = 0.207 padj = 0.345 |
B | β | R | R2 | ΔR2 | F | ΔF | t | |
---|---|---|---|---|---|---|---|---|
Step 1 | 0.422 | 0.178 | 0.178 | 1.623 (p = 0.194) | 1.623 (p = 0.194) | |||
Current age | 0.000 | −0.187 | −0.806 (p = 0.427) | |||||
Age at diagnosis | 0.001 | 0.329 | 1.561 (p = 0.129) | |||||
Sex | −0.003 | −0.129 | −0.710 (p = 0.483) | |||||
Cranial radiotherapy | 0.008 | 0.281 | 1.634 (p = 0.113) | |||||
Step 2 | 0.585 | 0.342 | 0.164 | 3.018 (p = 0.026) | 7.244 (p = 0.012) | |||
Current age | −0.001 | −0.316 | −1.463 (p = 0.154) | |||||
Age at diagnosis | 0.000 | −0.136 | −0.526 (p = 0.603) | |||||
Sex | −0.005 | −0.200 | −1.192 (p = 0.243) | |||||
Cranial radiotherapy | 0.007 | 0.253 | 1.619 (p = 0.116) | |||||
IT-MTX dose | 0.000 | −0.704 | −2.692 (p = 0.012) | |||||
Step 3 | 0.585 | 0.342 | 0.000 | 2.428 (p = 0.051) | 0.001 (p = 0.974) | |||
Current age | −0.001 | −0.316 | −1.435 (p = 0.162) | |||||
Age at diagnosis | 0.000 | −0.135 | −0.508 (p = 0.615) | |||||
Sex | −0.005 | −0.202 | −1.094 (p = 0.283) | |||||
Cranial radiotherapy | 0.007 | 0.254 | 1.584 (p = 0.124) | |||||
IT-MTX dose | 0.000 | −0.702 | −2.586 (p = 0.015) | |||||
Leucovorin dose | 0.000 | −0.006 | −0.033 (p = 0.974) | |||||
Step 4 | 0.585 | 0.343 | 0.000 | 1.694 (p = 0.147) | 0.008 (p = 0.992) | |||
Current age | −0.001 | −0.306 | −1.103 (p = 0.280) | |||||
Age at diagnosis | 0.000 | −0.111 | −0.295 (p = 0.770) | |||||
Sex | −0.005 | −0.203 | −1.059 (p = 0.299) | |||||
Cranial radiotherapy | 0.007 | 0.261 | 1.337 (p = 0.193) | |||||
IT-MTX dose | 0.000 | −0.692 | −2.001 (p = 0.056) | |||||
Leucovorin dose | 0.000 | −0.010 | −0.051 (p = 0.959) | |||||
IT-MTX dose × sex | 0.000 | 0.011 | 0.041 (p = 0.968) | |||||
IT-MTX dose × age at diagnosis | 0.000 | 0.026 | 0.101 (p = 0.921) |
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Laniel, J.; Sultan, S.; Sinnett, D.; Laverdière, C.; Krajinovic, M.; Robaey, P.; Duong, L.; Lippé, S. Cumulative Dosage of Intrathecal Chemotherapy Agents Predicts White Matter Integrity in Long-Term Survivors of Acute Lymphoblastic Leukemia: A PETALE Study. Cancers 2024, 16, 1208. https://doi.org/10.3390/cancers16061208
Laniel J, Sultan S, Sinnett D, Laverdière C, Krajinovic M, Robaey P, Duong L, Lippé S. Cumulative Dosage of Intrathecal Chemotherapy Agents Predicts White Matter Integrity in Long-Term Survivors of Acute Lymphoblastic Leukemia: A PETALE Study. Cancers. 2024; 16(6):1208. https://doi.org/10.3390/cancers16061208
Chicago/Turabian StyleLaniel, Julie, Serge Sultan, Daniel Sinnett, Caroline Laverdière, Maja Krajinovic, Philippe Robaey, Luc Duong, and Sarah Lippé. 2024. "Cumulative Dosage of Intrathecal Chemotherapy Agents Predicts White Matter Integrity in Long-Term Survivors of Acute Lymphoblastic Leukemia: A PETALE Study" Cancers 16, no. 6: 1208. https://doi.org/10.3390/cancers16061208
APA StyleLaniel, J., Sultan, S., Sinnett, D., Laverdière, C., Krajinovic, M., Robaey, P., Duong, L., & Lippé, S. (2024). Cumulative Dosage of Intrathecal Chemotherapy Agents Predicts White Matter Integrity in Long-Term Survivors of Acute Lymphoblastic Leukemia: A PETALE Study. Cancers, 16(6), 1208. https://doi.org/10.3390/cancers16061208