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Historical data are conflicting as to whether superior outcomes occur with cyclophosphamide (CY) + TBI compared to oral busulfan (BU)-based myeloablative conditioning regimens. IV BU with or without pharmacokinetic monitoring is better tolerated than oral BU. To test whether myeloablative IV BU-based conditioning regimens result in similar outcomes to traditional TBI-based conditioning, we conducted a prospective multi-center cohort study comparing these 2 approaches in patients with myeloid malignancies (AML, MDS, CML) undergoing matched related or unrelated donor blood or marrow transplants. All patients received myeloablative conditioning intensity (IV BU (>9mg/kg) plus Cy (≥60 mg/kg) or fludarabine (≥80 mg/mē); TBI (≥500cGy in a single fraction or ≥800 cGy fractionated) plus Cy (≥60 mg/kg) or etoposide (≥30 mg/kg)) and calcineurin-inhibitor based graft-versus host disease (GVHD) prophylaxis. The primary objective was to test the non-inferiority of overall survival after IV BU compared to TBI. From March 2009 to February 2011, 1,483 eligible patients were enrolled (IV BU, n=1025, TBI, n=458) from 120 transplant centers. The 2 cohorts were similar with respect to median age (45 years), gender (50% female), race (88% Caucasian), performance status (68% ≥90), and HCT-CI. Most patients had acute myeloid leukemia (68% BU, 78% TBI). Disease status was early (51%), intermediate (18%) and advanced (31%) and were balanced in both cohorts. Grafts were primarily PB (77%) from matched sibling (40%) or well-matched unrelated donors (48%), balanced in both cohorts. IV BU regimens were CY (59%) or Flu (41%) based. 2-yr probabilities of overall survival (95% CI), were 56% (53-60%) and 48% (43-54%) for IV BU and TBI, respectively (p=0.02). Corresponding probabilities of progression-free survival (PFS) were 49% (45-52%) and 44% (40-49%), (p=0.17). The incidence of hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) was 5% for BU and 1% for TBI; (p < 0.001). Outcomes were the same for BU+CY and BU+Flu regimens. There were no differences in engraftment of neutrophils or platelets, disease relapse, grade 2-4 acute or chronic GVHD. Multivariate Analysis (MVA) (adjusting for HCT-CI, disease and status, donor type, age, PS, and race) of the main outcomes is summarized in Table 2. Compared to TBI, IV BU was associated with superior survival and no increased risk of relapse or TRM. These results support the use of myeloablative BU- over TBI-based conditioning regimens for treatment of AML, MDS, and CML.
Cox Proportional Hazards MVA for IV BU vs. TBI
Outcome
| N
| IV BU vs. TBI HR (95% CI)
|
|
OM
| 1439
| 0.82 (0.68-0.98)
| 0.026
|
TRM
| 1434
| 0.81 (0.61-1.08)
| 0.15
|
Rel
| 1434
| 0.93 (0.76-1.12)
| 0.43
|
TF
| 1434
| 0.90 (0.77-1.06)
| 0.19
|
Abbreviations: HR (hazard ratio); N (number of subjects); OM (overall mortality); Rel (relapse); TF (treatment failure, relapse or death); TRM (treatment-related mortality)