Pharmacokinetic targeting of iv BU with fludarabine as conditioning before hematopoietic cell transplant: the effect of first-dose area under the concentration time curve … (original) (raw)
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Bone Marrow Transplantation, 2010
We used pharmacokinetic (PK) targeting of BU in 145 consecutive patients treated with fludarabine and i.v. BU. BU was given once daily at 130 mg/m 2 per day on days 1 and 2; doses for days 3 and 4 were adjusted in 92 patients (63%) to an average daily area under the concentration-time curve (AUC) of 5300 lM/min. In the remaining 53 patients, the first-dose AUC was within the target range and no dosing adjustments were required. First-dose AUC, maximum concentration and clearance were not correlated with age, race, ethnicity, performance status, or hematopoietic cell transplant comorbidity index. Women had higher clearance than men (median 2.9 vs 2.5 mL/min/kg; P ¼ 0.001). BU toxicities were not associated with first-dose AUC or any other PK parameter measured. First-dose BU AUC was not associated with non-relapse mortality (NRM) or survival, but higher AUC was predictive of relapse. We did not find an increased risk of toxicity or NRM in patients with high first-dose AUC presumably because of the dose adjustment. We conclude that PK targeting of BU as described here provides a simple, safe and effective method of delivering high BU doses before transplantation in a wide variety of patients.
Blood Advances, 2019
Fludarabine is the most frequently used agent in conditioning regimens for allogeneic hematopoietic cell transplantation (HCT). Body surface area–based dosing leads to highly variable fludarabine exposure. We studied the relation between fludarabine exposure and clinical outcomes. A retrospective, pharmacokinetic-pharmacodynamic analysis was conducted with data from patients undergoing HCT with fludarabine (160 mg/m2) as part of a myeloablative conditioning (busulfan targeted to an area under the plasma-concentration-time curve [AUC] of 90 mg*h/L) and rabbit antithymocyte globulin (6-10 mg/kg; from day −9/−12) between 2010 and 2016. Fludarabine exposure as AUC was calculated for each patient using a previously published population pharmacokinetic model and related to 2-year event-free survival (EFS) by means of (parametric) time-to-event models. Relapse, nonrelapse mortality (NRM), and graft failure were considered events. One hundred ninety-two patients were included (68 benign and...
Biology of Blood and Marrow Transplantation, 2002
The availability of an IV 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/m 2 on days -6 to -2 plus IV 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 IV 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 a second 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 m 2 , 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 µM × 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 PO Bu. This regimen incorporating once-daily IV Bu is convenient to give, is relatively well tolerated, gives predictable blood levels, and deserves further study in circumstances in which cytoreduction as well as immune suppression is needed.
Bone Marrow Transplantation, 2010
A pretransplant test dose of i.v. BU was previously used in pediatric patients undergoing a reduced-intensity allogeneic hematopoietic SCT (HSCT). Here, we used a BU test dose in 23 adult patients who were not pancytopenic and underwent a myeloablative allogeneic HSCT prepared with fludarabine and i.v. BU (FluBU). Pharmacokinetics (PK) of BU were calculated after a test dose (0.8 mg/kg) was performed 2 weeks before transplant. Targeted BU area under the curve (AUC) range was 4800-5200 lM min. The mean BU dose calculated after the test dose was 3.5 ± 0.5 mg/kg. To validate the test dose, PK studies were repeated in 17 patients after the first dose of BU during the conditioning regimen. An AUC below the therapeutic value of 4000 lM min was observed in 23% of the patients receiving a wt-based dose and in 0% of patients whose dose was calculated on the basis of the test dose (P ¼ 0.03). In patients who had a test dose, a significant correlation (Po0.0001) between the first and subsequent doses of BU during the conditioning regimen was observed. Our findings may allow more centers to pursue transplant strategies with targeted BU by overcoming the time limitation for PK studies during the conditioning regimen.
Translational Research, 2016
Patients undergoing hematopoietic cell transplantation (HCT) with reduced intensity conditioning (RIC) commonly receive fludarabine. Higher exposure of F-ara-A, the active component of fludarabine, has been associated with a greater risk of non-relapse mortality (NRM). We sought to develop a model for fludarabine dosing in adult HCT recipients that would allow for precise dose targeting and predict adverse clinical outcomes. We developed a pharmacokinetic model from 87 adults undergoing allogeneic RIC HCT that predicts F-ara-A population clearance (Clpop) accounting for ideal body weight and renal function. We then applied the developed model to an
Biology of Blood and Marrow Transplantation, 2011
We evaluated the impact of busulfan dose intensity in patients undergoing reduced toxicity/ intensity conditioning allogeneic transplantation in a multicenter retrospective study of 112 consecutive patients. Seventy-five patients were conditioned with busulfan (0.8 mg/kg/dose IV Â 8 doses), fludarabine (30 mg/m 2 /day, days À7 to À3), and 6 mg/kg of ATG [reduced intensity conditioning (RIC) group], while 37 patients received a more-intense conditioning with busulfan (130 mg/m 2 /day IV, days À6 to À3), fludarabine (40 mg/m 2 /day, days À6 to À3) and 6 mg/kg of ATG [reduced toxicity conditioning (RTC) group]. At baseline both groups were matched for median age, unrelated donor allografts, and human leukocyte antigen-mismatched allografts. More patients in RIC group had high-risk disease, and higher median comorbidity index. There were no graft rejections. Median time to neutrophil (17 days vs. 15 days; p ¼ 0.003) and platelet engraftment (16 days vs. 11 days; p < 0.001) was significantly longer in the RIC group. RTC group had significantly more bacterial (62.2% vs. 32%; p ¼ 0.004) and fungal infections (13.5% vs. 1.3% p ¼ 0.01). For RIC and RTC groups rates of grades II-IV acute GVHD (34% vs. 40%; p-value ¼ 0.54), and chronic GVHD (45% vs. 57%; p-value ¼ 0.30) were not significantly different. In similar order at 1 year the cumulative-incidence of non-relapse mortality (NRM; 12% vs. 21%; p-value ¼ 0.21) and relapse rates (38% vs. 39%; p ¼ 0.96) were not significantly different. Patients in RIC and RTC groups had similar 1-year overall survival (61% vs. 50%, p ¼ 0.11) and progression-free survival (50% vs. 36%, p-value ¼ 0.39). Our data suggest that the merits of higher busulfan dose intensity in the context of fludarabine/ busulfan-based RTC may be offset by higher early morbidity.
Biology of Blood and Marrow Transplantation, 2011
We aimed to evaluate the safety and efficacy of fludarabine (FLU) and pharmacokinetic-targeted busulfan (BU) as conditioning regimen for hematopoietic cell transplantation (HCT) in adult patients with acute lymphoid leukemia (ALL). Forty-four patients with ALL (27 in first complete remission [CR1] and 17 in more advanced disease stage: 4 with primary induction failure [PIF], 12 in CR2, and 1 in CR3) received FLU and pharmacokinetic-targeted BU as preparative therapy for HCT. Grafts were T-replete, filgrastim-mobilized peripheral blood stem cells (PBSC). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus (TAC) and short-course methotrexate in 36 patients, TAC and sirolimus in 3, and TAC and mycophenolate mofetil in 5. Primary engraftment was achieved in all 44 patients. The cumulative incidence of transplantrelated mortality (TRM) was 2% (95% confidence interval [CI] 0%-16%) at 100 days and 18% (95% CI 10%-34%) at 2 years. The 2-year cumulative incidence of relapse was 19% (95% CI 8%-41%) for those transplanted in CR1, and 48% (29%-80%) for those with more advanced disease. After a median follow-up of 32 months (range: 15-69 months), the 2-year overall survival (OS) was 54% (95% CI 39%-69%). Relapse-free survival (RFS) at 2 years was 63% (95% CI 45%-81%) for patients transplanted in CR1 and 34% (95% CI 11%-57%) for patients transplanted in more advanced disease. When compared to irradiation-containing regimens, FLU and PK-targeted BU appear safer and similarly effective in controlling ALL, providing a treatment option for adult patients with ALL.
Biology of Blood and Marrow Transplantation, 2014
Busulfan (Bu) is used as a myeloablative agent in conditioning regimens before allogeneic hematopoietic cell transplantation (allo-HCT). In line with strategies explored in adults, patient outcomes may be optimized by replacing cyclophosphamide (Cy) with or without melphalan (Mel) with fludarabine (Flu). We compared outcomes in 2 consecutive cohorts of HCT recipients with a nonmalignant HCT indication, a myeloid malignancy, or a lymphoid malignancy with a contraindication for total body irradiation (TBI). Between 2009 and 2012, 64 children received Flu þ Bu at a target dose of 80-95 mg$h/L, and between 2005 and 2008, 50 children received Bu targeted to 74-80 mg$h/L þ Cy. In the latter group, Mel was added for patients with myeloid malignancy (n ¼ 12). Possible confounding effects of calendar time were studied in 69 patients receiving a myeloablative dose of TBI between 2005 and 2012. Estimated 2-year survival and event-free survival were 82% and 78%, respectively, in the FluBu arm and 78% and 72%, respectively, in the BuCy (Mel) arm (P ¼ not significant). Compared with the BuCy (Mel) arm, less toxicity was noted in the FluBu arm, with lower rates of acute (noninfectious) lung injury (16% versus 36%; P ¼ .007), veno-occlusive disease (3% versus 28%; P ¼ .003), chronic graft-versus-host disease (9% versus 26%; P ¼ .047), adenovirus infection (3% versus 32%; P ¼ .001), and human herpesvirus 6 infection reactivation (21% versus 44%; P ¼ .005). Furthermore, the median duration of neutropenia was shorter in the FluBu arm (11 days versus 22 days; P < .001), and the patients in this arm required fewer transfusions. Our data indicate that Flu (160 mg/m 2) with targeted myeloablative Bu (90 mg$h/L) is less toxic than and equally effective as BuCy (Mel) in patients with similar indications for allo-HCT.