High Busulfan Exposure Is Associated with Worse Outcomes in a Daily i.v. Busulfan and Fludarabine Allogeneic Transplant Regimen

Geddes, Michelle; Kangarloo, Shahbal B.; Naveed, Farrukh; Quinlan, Dan; Chaudhry, M. Ahsan; Stewart, Douglas A.; Savoie, Mary Lynn; Bahlis, Nizar J.; Brown, Christopher B.; Storek, Jan; Andersson, Börje S.; Russell, James A.

doi:10.1016/j.bbmt.2007.10.028

Cited by 134 publications

(140 citation statements)

References 35 publications

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“…Toxicity and TRM are known to be increased in patients with high levels of BU, whereas relapse and graft rejection increase with low levels. [24][25][26] Prospective cohort studies are capable of accruing large number of patients and of measuring outcomes of contemporary transplant practices. Approximately 80% of patients undergoing transplantation in the United States who met eligibility criteria for the study during the accrual period were enrolled on this trial, providing an evaluation of these treatment approaches in the real world.…”

Section: Discussionmentioning

confidence: 99%

Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation

Bredeson

Le‐Rademacher

Kato

et al. 2013

Blood

136

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• Compared with TBI, IV-BU resulted in superior survival with no increased risk for relapse or TRM.• The results support the use of myeloablative IV-BU vs TBIbased conditioning regimens for treatment of myeloid malignancies.We conducted a prospective cohort study testing the noninferiority of survival of ablative intravenous busulfan (IV-BU) vs ablative total body irradiation (TBI)-based regimens in myeloid malignancies. A total of 1483 patients undergoing transplantation for myeloid malignancies (IV-BU, N 5 1025; TBI, N 5 458) were enrolled. Cohorts were similar with respect to age, gender, race, performance score, disease, and disease stage at transplantation. Most patients had acute myeloid leukemia (68% IV-BU, 78% TBI). Grafts were primarily peripheral blood (77%) from HLA-matched siblings (40%) or well-matched unrelated donors (48%). Two-year probabilities of survival (95% confidence interval [CI]), were 56% (95% CI, 53%-60%) and 48% (95% CI, 43%-54%, P 5 .019) for IV-BU (relative risk, 0.82; 95% CI, 0.68-0.98, P 5 .03) and TBI, respectively. Corresponding incidences of transplantrelated mortality (TRM) were 18% (95% CI, 16%-21%) and 19% (95% CI, 15%-23%, P 5 .75) and disease progression were 34% (95% CI, 31%-37%) and 39% (95% CI, 34%-44%, P 5 .08).The incidence of hepatic veno-occlusive disease (VOD) was 5% for IV-BU and 1% with TBI (P < .001). There were no differences in progression-free survival and graft-versus-host disease. Compared with TBI, IV-BU resulted in superior survival with no increased risk for relapse or TRM. These results support the use of myeloablative IV-BU vs TBI-based conditioning regimens for treatment of myeloid malignancies. (Blood. 2013;122(24):3871-3878)

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Section: Discussionmentioning

confidence: 99%

Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation

Bredeson

Le‐Rademacher

Kato

et al. 2013

Blood

136

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“…Additional studies evaluating BU were reviewed but did not report on cutaneous toxicity. 2,3,5,[7][8][9][10][11][12][13][14] Toxic erythema of chemotherapy after high-dose BU TL Parker et al development of erosions and desquamation may be the first sign of TEC; the former may be misdiagnosed as herpetic viral infections. Lastly, the duration of the cutaneous toxicity may be weeks and to date, we have found no specific therapy that alters the clinical course.…”

Section: Study (Year)mentioning

confidence: 99%

Toxic erythema of chemotherapy following i.v. BU plus fludarabine for allogeneic PBSC transplant

Parker

Cooper

Seropian

et al. 2012

Bone Marrow Transplant

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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 o5% 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 ( þ / À 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 þ / À ATG and it is important for transplant physicians to recognize, particularly as misdiagnosis could lead to inappropriate treatment.

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“…In the last decade, the use of oral busulfan, which was complicated by variable bioavailability, has been progressively replaced by that of the IV formulation. [12][13][14] However, data on the use of IV busulfan in children are limited and considerable inter-individual variability in busulfan exposure is still observed, especially in children. [15][16][17][18][19] Controlling patient exposure has become a major issue to improve efficacy and safety of busulfan-based conditioning.…”

Section: Introductionmentioning

confidence: 99%

Should busulfan therapeutic range be narrowed in pediatrics? Experience from a large cohort of hematopoietic stem cell transplant children

Philippe

Goutelle

Guitton

et al. 2015

Bone Marrow Transplant

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Busulfan, the corner stone of hematopoietic stem cell transplantation regimens, has a narrow therapeutic window. Therapeutic drug monitoring (TDM)-guided dosing to reach the conventional area under the concentration-time curve (AUC) target range of 900-1500 μmol min/L is associated with better outcomes. We report our experience with busulfan TDM in a large cohort of children. The aims were to investigate the relevance of using a more restricted therapeutic range and investigate the association between busulfan therapeutic range and clinical outcome. This study includes 138 children receiving 16 doses of intravenous busulfan, with the first dose assigned based on weight and doses adjusted to a local AUC target range of 980-1250 μmol min/L. Busulfan TDM combined with model-based dose adjustment was associated with an increased probability of AUC target attainment, for both target range: 90.8% versus 74.8% for the conventional target range and 66.2% versus 43.9% for the local target range (P o 0.001). The median follow-up was 56.2 months. Event-free survival was 88.5%, overall survival was 91.5% and venoocclusive disease occurred in 18.3% of patients. No difference was observed for clinical outcomes depending on the selected target range. Pharmacokinetic monitoring and individualization of busulfan dosage regimen are useful in improving target attainment, but using a restricted target range has no impact on clinical outcomes.

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High Busulfan Exposure Is Associated with Worse Outcomes in a Daily i.v. Busulfan and Fludarabine Allogeneic Transplant Regimen

Cited by 134 publications

References 35 publications

Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation

Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation

Toxic erythema of chemotherapy following i.v. BU plus fludarabine for allogeneic PBSC transplant

Should busulfan therapeutic range be narrowed in pediatrics? Experience from a large cohort of hematopoietic stem cell transplant children

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