What is the BuCy (Busulfan and Cyclophosphamide) conditioning regimen for hematopoietic stem cell transplantation?

BuCy Conditioning Regimen for Hematopoietic Stem Cell Transplantation

The standard BuCy (Busulfan-Cyclophosphamide) conditioning regimen consists of intravenous busulfan 0.8 mg/kg every 6 hours for 4 consecutive days (16 total doses, Days -7 to -4) followed by cyclophosphamide 60 mg/kg daily for 2 days (Days -3 and -2), with stem cell infusion on Day 0. 1

Standard Dosing Protocol

Busulfan Component

• Intravenous busulfan: 0.8 mg/kg administered every 6 hours for 16 doses over 4 consecutive days (Days -7, -6, -5, -4) 1, 2
• Dosing should be based on adjusted ideal body weight for obese patients: AIBW = IBW + 0.25 × (actual weight - IBW) 1
• Target area under the curve (AUC): 800-1500 μMol-min, with 86% of patients maintaining this therapeutic window with IV formulation 2
• Must be diluted to approximately 0.5 mg/mL concentration prior to administration 1

Cyclophosphamide Component

• Cyclophosphamide: 60 mg/kg/day for 2 consecutive days (Days -3 and -2) 1, 2
• Administered as 1-hour infusion beginning no sooner than 6 hours after the 16th busulfan dose 1
• Alternative dosing: 50 mg/kg/day for 2 days in modified regimens 3

Stem Cell Infusion

• Hematopoietic progenitor cells infused on Day 0 1
• Median time to neutrophil engraftment (ANC >0.5 × 10⁹/L): 10-13 days 2, 4

Essential Supportive Care

Seizure Prophylaxis (Mandatory)

• Anticonvulsants required starting 12 hours before first busulfan dose through 24 hours after last dose 1
• Options include benzodiazepines, phenytoin, valproic acid, or levetiracetam 1
• High-dose busulfan causes seizures without prophylaxis 1

Antiemetic Coverage

• Administer antiemetics prior to first busulfan dose 1
• Continue on fixed schedule throughout entire busulfan administration period 1

Clinical Indications

Primary Indications

• Chronic myelogenous leukemia as FDA-approved indication 1
• Acute myeloid leukemia in various disease stages 3, 2, 5
• Myeloid malignancies requiring myeloablative conditioning 3
• Multiple myeloma and non-Hodgkin lymphoma as alternative to BEAM or Flu/Mel regimens 6

Patient Selection Criteria

• Age <55 years for standard-intensity myeloablative conditioning 6
• Patients without significant organ dysfunction or HSCT-CI ≥3 6
• Both HLA-matched sibling and matched unrelated donors 2, 5

Modified BuCy Regimens

BuCy with ATG (for Non-Malignant Disorders)

• Severe aplastic anemia: Bu 6.4 mg/kg IV (Days -7, -6) + Cy 200 mg/kg (Days -5 to -2) + ATG 10 mg/kg (Days -5 to -2) 6
• Thalassemia: Bu 14 mg/kg PO + Cy 200 mg/kg total dose 6

Intensified BuCy Variants

• Addition of fludarabine 90 mg/m² and cytarabine 6 g/m² for high-risk myeloid malignancies showed 8-year disease-free survival of 67.9% 3
• Fludarabine-busulfan (FluBu): Flu 40 mg/m²/day × 5 days + Bu 4 mg/kg/day × 4 days as alternative with lower toxicity 4

Expected Outcomes

Efficacy

• 2-year overall survival: 67% across mixed-risk populations 2
• 2-year disease-free survival: 42-44% in phase II studies 2, 5
• Standard-risk patients (AML CR1, CML CP1): 63% 2-year event-free survival 5
• High-risk patients: 24% 2-year event-free survival with increased relapse risk 5

Engraftment

• 100% chimerism documented in evaluable patients 2
• Zero graft failures in properly dosed IV busulfan regimens 2
• Median neutrophil recovery: 13 days 2

Toxicity Profile and Management

Common Toxicities (Grades II-IV)

• Mucositis/stomatitis: 63-87% of patients, most common significant toxicity 5, 4
• Hepatic toxicity: 44% grades II-IV, including veno-occlusive disease risk 5
• Treatment-related mortality at 100 days: 3.5-9.8% 3, 2

Predictors of Increased Hepatic Toxicity

• Female sex (P=0.004 for hepatic toxicity) 5
• Amphotericin B use (P=0.01, strongest predictor in multivariate analysis) 5
• Methotrexate in GVHD prophylaxis (P=0.04) 5
• Prolonged antibiotic courses (P=0.04) 5

Fatal Complications

• Veno-occlusive disease: 2/61 patients (3.3%), particularly in prior transplant recipients 2
• Avoid in patients with pre-existing hepatic dysfunction 5

GVHD Prophylaxis and Incidence

Standard Prophylaxis

• Cyclosporine + methotrexate (4 doses IV on Days +1, +3, +6, +11) is gold standard for matched sibling donors 6
• Cyclosporine 3 mg/kg IV from Day -2 to +6, then 12 mg/kg PO until Day +60 4

GVHD Rates

• Acute GVHD grades II-IV: 21-49% 3, 5
• Acute GVHD grades III-IV: 8.8-31% 3, 5
• Chronic GVHD: 36.4% in evaluable patients 3

Critical Safety Considerations

Contraindications and Precautions

• Do not use polycarbonate infusion components with busulfan—drug incompatibility 1
• Use administration sets with minimal hold-up volume (2-5 mL) 1
• Severe myelosuppression is expected and required—transplant is mandatory 1

Handling Requirements

• Cytotoxic drug requiring special handling procedures 1
• Wear gloves during preparation 1
• If skin/mucosa contact occurs, wash thoroughly with water immediately 1

Comparison with Alternative Regimens

BuCy vs. TBI-Based Conditioning

• Transplant-related mortality significantly lower with cyclophosphamide-TBI (CYTBI) compared to oral BuCy (RR=0.53,95% CI: 0.31-0.90, P=0.02) 7
• However, no significant difference in overall survival between regimens (RR=0.82, P=0.12) 7
• IV busulfan formulation addresses the erratic absorption issues of oral busulfan that contributed to inferior outcomes 2
• TBI-based regimens cause more severe late effects on growth/development in children 7

Advantages of IV Busulfan Over Oral

• Predictable pharmacokinetics with high inter- and intrapatient consistency 2
• Complete bioavailability vs. erratic GI absorption with oral formulation 2
• Dose assurance leading to improved efficacy and reduced toxicity 2