Maximally Tolerated Busulfan Systemic Exposure in Combination with Fludarabine as Conditioning before Allogeneic Hematopoietic Cell Transplantation

Department of Blood and Marrow Transplantation, Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL 33612, USA.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation (Impact Factor: 3.4). 12/2011; 18(7):1099-107. DOI: 10.1016/j.bbmt.2011.12.584
Source: PubMed


Systemic exposure to high-dose busulfan has been correlated with efficacy and toxicity after hematopoietic cell transplantation for malignancy. We used the area under the concentration-time curve (AUC) to prospectively determine the maximally tolerated systemic exposure to i.v. busulfan when given once daily after fludarabine administered at 40 mg/m(2) for 4 days. Three target AUC levels were planned: 6,000, 7,500, and 9,000 μM-min. Included were patients 16 to 65 years old, with a hematologic malignancy, an HLA A, B, or C, DRB1 8/8 or 7/8 matched donor, Karnofsky performance status ≥70%, and adequate organ function. For level 1 patients, i.v. busulfan doses 1 and 2 were 170 mg/m(2)/day, then doses 3 and 4 were adjusted based on first-dose pharmacokinetic modeling to achieve an average daily AUC of 6,000 μM-min. Doses 1 and 2 for the subsequent cohorts were based on the level 1 data: 180 mg/m(2)/day for AUC 7,500 μM-min (level 2) and 220 mg/m(2)/day for AUC 9,000 μM-min (level 3), with pharmacokinetic targeting for doses 3 and 4. Pharmacokinetic analysis after the last dose showed that 88% of the patients had been exposed to a mean AUC within 10% of the target. Forty patients were treated at level 1, 29 patients at level 2, and three patients at level 3. DLT was veno-occlusive disease of the liver, which occurred in none of 40 patients (0%) at level 1, two of 29 patients (7%) at level 2, and three of three patients (100%) at level 3. Dermatitis (P < .01) and pulmonary toxicity (P = .01) were also increased at higher AUC levels. Level 2 (7,500 μM-min × 4 days) was the maximally tolerated AUC. Within the confines of the trial's small sample size, there was no suggestion that escalating busulfan AUC from 6,000 to 7,500 μM-min × 4 days increased nonrelapse mortality. Assessment of the higher busulfan AUC on relapse prevention requires trials in patients with a homogeneous risk of relapse.

3 Reads
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: I.v. BU plus fludarabine is an effective conditioning regimen for myeloid neoplasias with low treatment-related mortality. At standard doses, cutaneous toxicity has been reported in <5% of cases. As we observed a much higher incidence of cutaneous toxicity in patients who received predominantly pharmacokinetically based doses of BU, we performed a retrospective analysis of 61 patients who received i.v. BU plus fludarabine (+/- antithymocyte globulin; ATG) as a conditioning regimen before allogeneic PBSC transplant. Of the 58 evaluable patients, 33 (57%) developed cutaneous toxicity that fell within the spectrum of toxic erythema of chemotherapy (TEC). The median onset of TEC was 22 days and most patients had multiple sites of involvement, with the groin, axillae and palms/soles being the favored sites. In men, scrotal involvement, sometimes severe, was also commonly observed. Initially, allergic reactions to antibiotics, fungal infections and GVHD were also considered until the clinical presentation of TEC became well recognized. In all patients, the skin healed without specific therapy but resolution often required several weeks. This series suggests that TEC is common after BU/fludarabine+/- ATG and it is important for transplant physicians to recognize, particularly as misdiagnosis could lead to inappropriate treatment.Bone Marrow Transplantation advance online publication, 19 November 2012; doi:10.1038/bmt.2012.218.
    Bone marrow transplantation 11/2012; 48(5). DOI:10.1038/bmt.2012.218 · 3.57 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Targeted busulfan/cyclophosphamide ((T)BU/CY) for allogeneic hematopoietic cell transplantation (HCT) carries a high risk of sinusoidal obstruction syndrome (SOS) in patients transplanted for myelofibrosis. We tested the hypothesis that reversing the sequence of administration (from (T)BU/CY to CY/(T)BU) will reduce SOS and day +100 non-relapse mortality (NRM). We enrolled 51 patients with myelofibrosis (n=20), acute myeloid leukemia (AML, n=20), or myelodysplastic syndrome (MDS, n=11) in a prospective trial of CY/(T)BU conditioning for HCT. Cyclophosphamide 60 mg/kg/day IV for two days was followed by daily IV BU for four days, targeted to a concentration at steady state (Css) of 800-900 ng/mL. CY/(T)BU-conditioned patients had higher exposure to CY (p<0.0001) and lower exposure to 4-hydroxyCY (p<0.0001) compared to (T)BU/CY-conditioned patients. Clinical outcomes were compared with controls (n=271) conditioned with (T)BU/CY for the same indications. In patients with myelofibrosis, CY/(T)BU conditioning was associated with a significantly reduced incidence of SOS (0% vs. 30% after (T)BU/CY, p=0.006), while SOS incidence was low in both cohorts with AML/MDS. Day +100 mortality was significantly lower in the CY/(T)BU cohort (2% vs. 13%, p=0.01). CY/(T)BU conditioning markedly impacted CY pharmacokinetics and was associated with significantly lower incidences of SOS and day +100 mortality, suggesting that CY/(T)BU is superior to (T)BU/CY as conditioning for patients with myelofibrosis.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 04/2013; 19(7). DOI:10.1016/j.bbmt.2013.04.005 · 3.40 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A combination of fludarabine (Flu) and daily i.v. busulfan (Bu) is well tolerated and effective in patients receiving allogeneic transplantation. While we have some evidence that Bu exposures >6000 μM.min may lead to excessive toxicitythere is little information on the effect of exposures below this level on outcome.We studied Bu exposure, as measured by area under the concentration-timecurve (AUC) in 158 patients with a variety of hematologic malignancies in order to find an optimal range for targeted therapy. The preparative chemotherapy comprised Flu 50 mg/m2 on days -6 to -2 and i.v. Bu 3.2 mg/kg on days -5 to -2 inclusive. GVHD prophylaxis included methotrexate, CsA and Thymoglobulin. Patients with below median Bu exposures of 4440 μM.min had increased hazard of acute GVHD grade II-IV (HR=2.30, 95% CI: 1.19 to 4.49, p=0.014). Those in the highest and lowest Bu exposure quartiles (daily AUC below 3814 μM.min or above 4993 μM.min) had an increased risk of NRM (SHR=3.32, 95% CI: 1.46 to 7.54, p=0.004), as well as worse DFS (HR=1.81, 95% CI: 1.09 to 2.99, p=0.021) and OS (HR=1.94, 95% CI: 1.12 to 3.37, p=0.018). Bu exposures between 4440 and 4993 μM.min were accompanied by the lowest risk of both NRM and aGVHD.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 07/2013; 19(9). DOI:10.1016/j.bbmt.2013.07.002 · 3.40 Impact Factor
Show more

Preview (2 Sources)

3 Reads
Available from