Once-Daily Versus Four-Times-Daily Intravenous Busulfan with Therapeutic Drug Monitoring as Conditioning for Hematopoietic Cell Transplantation in Children
Abstract
1. Introduction
2. Materials and Methods
3. Results
3.1. Patients and Transplant Characteristics
3.2. Event-Free Survival
3.3. Stem Cell Engraftment
3.3.1. Neutrophil Engraftment
3.3.2. Platelet Engraftment
3.4. Incidence of Acute Graft-Versus-Host Disease (aGVHD)
3.5. Dose Adjustments of Busulfan Based on MIPD
3.6. Treatment-Related Adverse Events
3.7. Drug-Drug Interactions
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
Abbreviation | Full Term/Definition |
AUC | Area under the concentration–time curve |
AUC0–24 | Area under the concentration–time curve from 0 to 24 h |
ALK | Alkaline phosphatase |
ALT | Alanine transaminase |
AML | Acute myeloid leukemia |
ANC | Absolute neutrophil count |
aGVHD | Acute graft-versus-host disease |
ATG | Anti-thymocyte globulin |
Allo | Allogeneic |
BM | Bone marrow |
BU | Busulfan |
BU1 | Busulfan once daily |
BU4 | Busulfan four times daily |
BU–FLU | Busulfan–Fludarabine |
BU/MEL | Busulfan–Melphalan |
BU/MEL/CYC | Busulfan–Melphalan–Cyclophosphamide |
BU/TT | Busulfan–Thiotepa |
BSA | Body surface area |
Cmax | Maximum (peak) plasma concentration |
CGD | Chronic granulomatous disease |
CI | Confidence interval |
CYC | Cyclophosphamide |
CNS | Central nervous system |
CSA | Cyclosporine |
CSA–MMF | Cyclosporine with mycophenolate |
DNA | Deoxyribonucleic acid |
DDI | Drug–drug interaction |
EFS | Event-free survival |
EMA | European Medicines Agency |
FDA | Food and Drug Administration |
FLU | Fludarabine |
GVHD | Graft-versus-host disease |
H | Hour |
HLH | Hemophagocytic lymphohistiocytosis |
HLA | Human leukocyte antigen |
HR | Hazard ratio |
HSCT | Hematopoietic stem cell transplantation |
IQR | Interquartile range |
IV | Intravenous |
JMML | Juvenile myelomonocytic leukemia |
L/kg | Liter per kilogram |
MEL | Melphalan |
MDS | Myelodysplastic syndromes |
MIPD | Model-informed precision dosing |
mL/min/kg | Milliliter per minute per kilogram |
m2 | Square meter |
MMF | Mycophenolate mofetil |
MPS 1 | Mucopolysaccharidosis type I |
MTX | Methotrexate |
N | Number of patients |
NPD | Niemann–Pick disease |
PBSC | Peripheral blood stem cells |
PID | Primary immunodeficiency |
PK | Pharmacokinetics |
PO | Per os (by mouth) |
PRN | Pro re nata (as needed) |
Q6H | Every 6 h |
RNA | Ribonucleic acid |
SCID | Severe combined immunodeficiency |
SD | Standard deviation |
SOS | Sinusoidal obstruction syndrome |
SPSS | Statistical Package for the Social Sciences |
TT | Thiotepa |
ULN | Upper limit of normal |
VPA | Valproic acid |
Appendix A
Diseases Classification
- Inborn errors of immunity (severe combined immunodeficiency (SCID), primary immunodeficiency (PID), X-linked lymphoproliferative disease (XLP), chronic granulomatous disease (CGD), hemophagocytic lymphohistiocytosis (HLH), Wiskott–Aldrich syndrome).
- Metabolic disorders (osteopetrosis, alpha-mannosidosis, X-related adrenoleukodystrophy (ALD), metachromatic leukodystrophy (MLD), Krabbe leukodystrophy, mucopolysaccharidosis Type I (MPS 1), Niemann–Pick disease (NPD)).
- Non-malignant hematological disorders (pure red cell aplasia (PRCA), aplastic anemia, sideroblastic anemia, Diamond–Blackfan anemia (DBA), congenital amegakaryocytic thrombocytopenia (CAMT)).
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Patient Characteristics | BU4 n = 35 (%) | BU1 n = 35 (%) | p-Value |
---|---|---|---|
Age at HSCT, median (years)—(25th–75th Percentile (IQR)) | 3.85 (1.18–8.29 (7.11)) | 4.83 (3.08–6.6 (3.52)) | 0.304 |
Follow up, median (days)—(25th–75th Percentile (IQR)) | 1169 (343–1587 (1244)) | 267 (174–537 (363)) | <0.001 |
Age group (years) | 0.397 | ||
<2 years | 12 (34.3%) | 7 (20%) | |
2–<6 years | 10 (28.6%) | 13 (37.1%) | |
6–18 years | 13 (37.1%) | 15 (42.9%) | |
Sex | 0.131 | ||
Male | 20 (57.1%) | 26 (74.3%) | |
Female | 15 (42.9%) | 9 (25.7%) | |
Body surface area, median (m2)—(25th–75th Percentile (IQR)) | 0.59 (0.44–0.92 (0.48)) | 0.72 (0.59–0.93 (0.34)) | 0.147 |
Diagnosis | 0.794 * | ||
Malignant Diseases: | 11 (31.4%) | 10 (28.6%) | |
Leukemia | 5 | 6 | |
Solid tumors | 6 | 4 | |
Non-malignant Diseases: | 24 (68.6%) | 25 (71.4%) | |
Inborn errors of immunity | 14 | 6 | |
Metabolic disorders | 5 | 17 | |
Non-malignant hematological disorders | 5 | 2 |
Transplant Characteristics | BU4 n = 35 (%) | BU1 n = 35 (%) |
---|---|---|
Type of HSCT | ||
Allogeneic | 30 (85.7%) | 31 (88.6%) |
Autologous | 5 (14.3%) | 4 (11.4%) |
Conditioning Protocol | ||
BU-FLU | 20 (57.1%) | 20 (57.1%) |
BU-MEL | 5 (14.3%) | 4 (11.4%) |
BU-CYC-MEL | 5 (14.3%) | 5 (14.3%) |
BU-FLU-CYC | 0 (0%) | 5 (14.3%) |
BU-FLU-TT | 5 (14.3%) | 1 (2.9%) |
Allogeneic Patients | AlloBU4 n = 30 (%) | AlloBU1 n = 31 (%) |
Donor Source Cells | ||
BM | 23 (76.7%) | 16 (51.6%) |
PBSC | 6 (20%) | 5 (16.1%) |
Cord | 1 (3.3%) | 10 (32.3%) |
Type of Donor | ||
Related donor | 16 (53.3%) | 10 (32.3%) |
Unrelated donor | 14 (46.7%) | 21 (67.7%) |
HLA Matching | ||
Full matched donor | 23 (76.7%) | 23 (74.2%) |
Haploidentical | 4 (13.3%) | 2 (6.5%) |
Mismatched donor | 3 (10%) | 6 (19.4%) |
Immunosuppressive Therapy | ||
Yes: | 27 (90%) | 29 (93.5%) |
ATG | 20 | 25 |
Alemtuzumab | 7 | 4 |
GVHD Prophylaxis | ||
CSA-MMF | 17 (56.7%) | 22 (70.9%) |
CSA-MTX | 6 (20%) | 6 (19.4%) |
CSA only | 5 (16.7%) | 3 (9.7%) |
CSA-MTX-MMF | 2 (6.7%) | 0 (0%) |
Busulfan Adverse Events | BU4–n = 35 (%) | BU1–n = 35 (%) |
---|---|---|
Fever | 33 (94.3%) | 32 (91.4%) |
Headache | 6 (17.1%) | 3 (8.6%) |
Chills | 8 (22.9%) | 5 (14.3%) |
Pain | 25 (71.4%) | 27 (77.1%) |
Edema | 6 (17.1%) | 4 (11.4%) |
Refractory Thrombocytopenia | 9 (25.7%) | 7 (20.0%) |
Tachycardia | 5 (14.3%) | 3 (8.6%) |
Hypertension | 7 (20.0%) | 5 (14.3%) |
Thrombosis | 2 (5.7%) | 2 (5.7%) |
Mucositis | 35 (100%) | 35 (100%) |
Stomatitis | 12 (34.3%) | 14 (40.0%) |
Nausea | 15 (42.9%) | 17 (48.6%) |
Vomiting | 14 (40.0%) | 16 (45.7%) |
Diarrhea | 18 (51.4%) | 20 (57.1%) |
Constipation | 11 (31.4%) | 13 (37.1%) |
Abdominal Pain | 6 (17.1%) | 8 (22.9%) |
Abdominal Enlargement | 2 (5.7%) | 2 (5.7%) |
Metabolic and Nutritional System | ||
Hypomagnesemia | 21 (60.0%) | 20 (57.1%) |
Hypokalemia | 18 (51.4%) | 17 (48.6%) |
Hypocalcemia | 4 (11.4%) | 5 (14.3%) |
Hyperbilirubinemia | 3 (8.6%) | 3 (8.6%) |
Creatinine Increased | 7 (20.0%) | 6 (17.1%) |
Respiratory System | ||
Epistaxis | 4 (11.4%) | 4 (11.4%) |
Dyspnea | 6 (17.1%) | 7 (20.0%) |
Others | ||
Rash | 9 (25.7%) | 10 (28.6%) |
Seizures | 0 (0.0%) | 1 (2.9%) |
Infections | ||
Bacterial Infections | 10 (28.6%) | 8 (22.9%) |
Fungal Infections | 6 (17.1%) | 4 (11.4%) |
Viral Infections | 12 (34.3%) | 9 (25.7%) |
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Bazbaz, S.; Zaidman, I.; Even-Or, E.; Stepensky, P.; Sakran, R.; Kurnik, D.; Aldouby-Bier, G. Once-Daily Versus Four-Times-Daily Intravenous Busulfan with Therapeutic Drug Monitoring as Conditioning for Hematopoietic Cell Transplantation in Children. Pharmaceutics 2025, 17, 1081. https://doi.org/10.3390/pharmaceutics17081081
Bazbaz S, Zaidman I, Even-Or E, Stepensky P, Sakran R, Kurnik D, Aldouby-Bier G. Once-Daily Versus Four-Times-Daily Intravenous Busulfan with Therapeutic Drug Monitoring as Conditioning for Hematopoietic Cell Transplantation in Children. Pharmaceutics. 2025; 17(8):1081. https://doi.org/10.3390/pharmaceutics17081081
Chicago/Turabian StyleBazbaz, Safaa, Irina Zaidman, Ehud Even-Or, Polina Stepensky, Razan Sakran, Daniel Kurnik, and Gefen Aldouby-Bier. 2025. "Once-Daily Versus Four-Times-Daily Intravenous Busulfan with Therapeutic Drug Monitoring as Conditioning for Hematopoietic Cell Transplantation in Children" Pharmaceutics 17, no. 8: 1081. https://doi.org/10.3390/pharmaceutics17081081
APA StyleBazbaz, S., Zaidman, I., Even-Or, E., Stepensky, P., Sakran, R., Kurnik, D., & Aldouby-Bier, G. (2025). Once-Daily Versus Four-Times-Daily Intravenous Busulfan with Therapeutic Drug Monitoring as Conditioning for Hematopoietic Cell Transplantation in Children. Pharmaceutics, 17(8), 1081. https://doi.org/10.3390/pharmaceutics17081081