Once-daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation: Study of pharmacokinetics and early clinical outcomes

Abstract

The availability of an i.v. form of busulfan (Bu) has prompted investigation of administration schedules other than the 4-times-daily dosage commonly used with oral Bu. We have studied an allogeneic stem cell transplantation (SCT) preparative regimen comprising fludarabine (FLU) 50 mg/m2 on days -6 to -2 plus i.v. Bu 3.2 mg/kg daily in a 3-hour infusion on days -5 to -2. The regimen was given to 70 patients aged 15 to 64 years (median, 41 years) with hematologic malignancy. Thirty-six patients (51%) had high-risk malignancy, 28 (40%) had unrelated or genotypically mismatched related donors (alternate donors [AD]) and 29 (41%) received bone marrow rather than blood as stem cell source. Acute GVHD prevention comprised antithymocyte globulin 4.5 mg/kg over 3 days pretransplantation, cyclosporin A, and short-course methotrexate with folinic acid. Hepatic toxicity was transient and there was no clinically diagnosed veno-occlusive disease. Grade II stomatitis occurred in 49 patients (70%) and hemorrhagic cystitis in 9 patients (13%). One patient with subtherapeutic phenytoin levels had a convulsion 8 hours after the third i.v. Bu dose, but no other neurotoxicity was apparent. Incidence of acute GVHD grades II to IV was 8% and incidence of grade III-IV was 3%, with no deaths from this cause. Actuarial incidence of chronic GVHD at 2 years is 38%. There were 2 cases of graft failure in unrelated donor BMT recipients, 1 of which was reversed by asecond transplantation. With a median follow-up of 16 months (range, 6-27 months), transplantation-related mortality at 100 days and 2 years was 2% and 5% for matched related donor (MRD) SCT and 8% and 19% for AD SCT, respectively (P = not significant). Relapse rates were 21% for 34 patients with acute myeloid leukemia (AML) in complete remission or chronic myeloid leukemia in chronic phase (low-risk), 66% for 19 patients with high-risk AML, and 18% for 17 patients with other active malignancy. Projected disease-free and overall survival rates at 2 years were 74% and 88% for low-risk disease, 26% and 37% for advanced AML, and 65% and 71% for other high-risk disease, respectively. Pharmacokinetic studies were done using 11 samples with the first and fourth doses of Bu. Kinetics were linear, and for the first and fourth doses, the half-lives were 2.60 +/- 0.44 and 2.57 +/- 0.36 hours, respectively. Clearances were 106.77 +/- 16.68 and 106.86 +/- 21.57 mL/min per m2, peak concentrations (Cmax) were 3.92 +/- 0.31 and 3.96 +/- 0.28 mcg/mL, and Bu areas under the plasma concentration versus time curve (AUC) were 4866.51 +/- 771.42 and 4980 +/- 882.80 microM x min, respectively. Bu was completely cleared within 24 hours and the day 4 pharmacokinetic values were very similar to those on day 1 for every patient. The cumulative AUC was comparable to the target range established for p.o. Bu. This regimen incorporating once-daily i.v. Bu is convenient to give, is relatively well tolerated, gives predictable blood levels, and deserves further study in circumstances in which cytoreduction as wel...

Single center retrospective analysis of BU-based conditioning regimens in allogeneic transplantation

“…Although i.v. BU had been reported to result in a lower incidence of VOD, 8 our results show that there was no significant difference between oral and i.v. BU administration in the development of VOD, 12.5% (n ¼ 9) vs 18.4% (n ¼ 7), respectively (P ¼ 0.15).…”

“…preparations have been shown to produce predictable blood levels, lower incidence of VOD and similar immunosuppressive effects. 8 Other factors that influence HSCT outcomes include the types of chemotherapeutic drugs that are used together with BU in the pre-transplant conditioning regimen. Since 1978, the use of BU and CY (BuCy) as a pretransplant conditioning regimen was adopted widely in transplant centers worldwide due to its ease of administration and good efficacy.…”

“…[11][12][13] Many studies in the past have addressed the pharmacokinetics, efficacy and early clinical outcomes of various BUbased conditioning regimens. 8,14,15 More recently, studies have individually compared the route of administration (oral or i.v. ), the combination (BuCy or BuFlu) and the dosage (high dose or low dose) of BU-based conditioning regimens.…”

Hematopoietic cell transplantation for patients with myelodysplastic syndromes (MDS): When, how and for whom?

“…BU, 3.2 mg/ kg, given once a day on 4 consecutive days (concurrently with Flu), combined with rabbit antithymocyte globulin, 4.5 mg/kg, plus methotrexate (MTX) and cyclosporine (CSP) for GVHD prophylaxis. 26 The study enrolled 70 patients with various diagnoses, including MDS. The mortality at day 100 was 2% with related donors and 8% with unrelated donors.…”

Age-dependent pharmacokinetic profile of single daily dose i.v. busulfan in children undergoing reduced-intensity conditioning stem cell transplant

“…BU has been shown to be a convenient and effective alternative. [16][17][18][19][20][21] A better understanding of the PK profile of i.v. BU when administered as a single daily dose will facilitate its use.…”