Individualized Once-Daily Dosing of Intravenous Busulfan: A Pharmacokinetic Study in Patients Undergoing Conditioning for Allogeneic Stem Cell Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 98-98 ◽  
Author(s):  
Shabal B. Kangarloo ◽  
Farrukh Naveed ◽  
Borje S. Andersson ◽  
Diana Quinlan ◽  
James A. Russell
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Correction Factor ◽  
Half Life ◽  
Therapeutic Dose ◽  
Test Dose ◽  
High Dose ◽  
Once Daily ◽  
Concentration Time ◽  
The Mean

Abstract Background: Busulfan (Bu) given in myeloablative doses is a frequent component of preparative regimens for hematopoietic stem cell transplantation. Variations in the area under the concentration/time curve (AUC) for oral Bu may result in over/under dosing, which may increase the risk of toxicity or reduce efficacy. The availability of an IV formulation of busulfan reduces this by eliminating variability in absorption but inter-patient differences in metabolism remain. A pharmacokinetically guided test dose strategy before the high dose Bu may be used to achieve a specific target AUC. Purpose: To establish a reliable model to predict a therapeutic dose of IV Bu from a small test dose in order to improve inter-patient variability in AUC. Methods: Pharmacokinetic (PK) analysis was performed on 35 paired patient samples, comparing a limited sampling test dose to the therapeutic high dose. For the test dose, an AimPlus infusion pump was used to administer 12 mg of IV Bu over a 20-minute infusion on day −6. High dose Bu was given at a dose of 3.2mg/kg daily over 4 hours on days −5 to −2. The test dose PK parameters were compared to the high dose IV Bu PK parameters on day −3. Busulfan concentrations in plasma were determined by UV-HPLC. All concentration-time plasma Bu data were analyzed by non-compartmental analysis using WinNonlin Version 4.1 software (Pharsight Corporation, Mountain View, CA, USA). Results: The mean (CV%) PK parameters for the 12 mg test dose patients were as follows: Cmax, 0.36 ug/mL (30.4%); clearance (CL), 16.3 L/hr (21.4%); volume of distribution Vd, 57.4 L (26.1%); elimination half-life, 2.4 hr (16.1%); and AUC, 199 μM.min (23.6%). The mean (CV%) Cmax, CL, Vd, half-life, and AUC for the once daily high dose were 3.95 ug/mL (22%), 11.7 L/hr (25.4%), 46.3 L (25.3%), 2.8 hr (15.6%), and 5190 μM.min (22.7%) respectively. The range of AUC for the high dose was 2832 to 7354 μM.min. The ratio of the high dose over the test dose required a correction factor “k” of 1.45 to be equivalent to the ratio of the AUC high dose over the AUC test dose. Conclusion: Dosing based on patient weight results in 2–3 fold variability of AUC. The fact that a correction factor based on the test dose is needed is most likely due to the statistically significantly higher CL of busulfan during the test dose as compared to the high dose CL. This raises questions concerning the proposed linear kinetics of IV busulfan. However using the above correction factor and given a target therapeutic AUC, it is possible to individualize the therapeutic dose for IV busulfan based on this test dose strategy.

Pre-Transplant Test Dose vs. PK Studies during Conditioning Regimen To Target iv Busulfan in Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3006-3006
Author(s):  
Sandeep Chunduri ◽  
Rakesh Beri ◽  
Lisa C. Dobogai ◽  
Elizabeth Hurter ◽  
Christina Mactal-Haaf ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Conditioning Regimen ◽  
Test Dose ◽  
Hematopoietic Stem ◽  
Blood Samples ◽  
The Mean

Abstract In this study we tested the efficacy of a test dose of iv busulfan in targeting blood levels of this drug during the conditioning regimen prior to an allogeneic hematopoietic stem cell transplant. We analyzed blood samples of 22 patients undergoing allogeneic hematopoietic stem cell transplantation with a busulfan-based conditioning regimen. Patients received a test dose of busulfan at 0.8 mg/kg as a 60 minute intravenous infusion. Serial blood samples were drawn at eight time points: 15 minutes before dose, at end of infusion, 15 minutes after completion, 30 minutes after completion, 60 minutes after completion, 2 hours after completion, 4 hours after completion, and 6 hours after completion. Pharmacokinetics (PK) studies were then performed at the Seattle Cancer Care pharmacokinetics laboratory. The AUC was determined using WinNonlin Professional software. The conditioning dose of busulfan was calculated by multiplying the test dose in mg/AUC × 4800. After the first dose of busulfan was administered, the same protocol was used to test busulfan PK. If the Busulfan AUC was therapeutic (between 4800 μM*min and 5200 μM*min) then the same dose was continued. If the Busulfan AUC was low or high then the third and fourth doses of busulfan were adjusted. The test dose of 0.8 mg/kg intravenous did not have any hematological side effects. The mean historic dose (solely based on weight) was 3.2 ± 0.1 mg/kg and the mean dose based on the test dose was 3.5 ± 0.5 mg/kg (p=0.02). In 12 patients where we also analyzed PK after the first day of conditioning regimen, AUC values of busulfan obtained during test dose and after day 1 dose were not different (p=0.7). The mean dose of busulfan based on test dose was 3.5 ± 0.6 mg/kg while the final dose based on day 1 busulfan PK was 3.6 ± 0.7 mg/kg (p=0.9). Nevertheless, in 2 CML patients who were on treatment with dasatinib or nilotinib at the time of the test dose, a higher AUC was observed (AUC 6065 and 6200, respectively). A pre-transplant busulfan test dose can be safely performed anytime prior to transplant and allows targeting the dose of busulfan efficiently, thus avoiding the requirement of PK studies during the conditioning regimen.

A Randomized Phase II Study Evaluating the Efficacy, Safety and Cost-Effectiveness of Pegfilgrastim and Filgrastim After High Dose Chemotherapy and Autologous Stem Cell Transplantation In Patients with Lymphoma and Myeloma (PALM Study).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3479-3479
Author(s):  
Catherine Sebban ◽  
Anne Lefranc ◽  
Lionel Perrier ◽  
Philippe Moreau ◽  
Daniel Espinouse ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cost Effectiveness ◽  
Stem Cell Transplantation ◽  
Sample Size ◽  
Clinical Outcomes ◽  
Autologous Stem Cell Transplantation ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Randomized Phase Ii ◽  
The Mean

Abstract Abstract 3479 Objective: To assess the efficacy, safety, and cost-effectiveness of a single injection of Pegfilgrastim (P) 6mg given at D5 or Filgrastim (F) 5μg/kg/day subcutaneously from D5 to the end of neutropenia after reinjection of stem cells in patients with lymphoma or myeloma. Patients and methods: The PALM study was an open, multicentre randomized phase II trial. Patients had to be at least 18 years old, with a diagnosis of lymphoma or myeloma, a cryopreserved graft of at least 2.10 CD34/kg, must have had a conditioning regimen without irradiation and an intensive chemotherapy. Eligible pts were 1:1 randomly assigned to P 6mg subcutaneously at D5 or F 5μg/kg/day subcutaneously from D5 to the end of neutropenia (absolute neutrophil count (ANC) >0.5G/L). Randomization was stratified on underlying disease and center. The primary efficacy endpoint was the mean duration of febrile neutropenia (FN) defined as ANC <0.5 G/L and temperature >38°C. Assuming a mean duration of FN of 4 days (SD 3.7), sample size (75 pts per arm) was calculated in order to estimate, with a precision of 0.85 day, a two-sided 95% confidence interval on the mean duration of FN in P arm. No formal comparison between arms was planned for the primary endpoint. The randomization was intended to afford a substantial degree of re-assurance that the historical control value chosen to plan the sample size was appropriate. Key secondary objectives were to estimate, for each treatment regimen, the respective tolerance profile and to compare the cost-effectiveness of the two strategies. The time horizon of the clinical and cost-effectiveness analysis was 100 days. All analyses were performed in the intent-to-treat population, which included all randomly assigned patients. For the economic assessments, a microcosting approach from the hospital perspective was used. Costs (2009 Euros) between P and F were compared using a Mann-Whitney U nonparametric test. Probabilistic sensitivity analyses were conducted using 1000 non-parametric bootstrap replications. Results: From October 2008 to September 2009, 151 pts were randomized. Clinical and demographic data were similar in both groups except for older age in the P arm. No grade 3 or 4 adverse event related to the drugs was notified. Data suggested that patients receiving P had similar or slightly better clinical outcomes. Especially, mean duration of FN were 3.07 (SD 1.96) and 3.29 (SD 2.54) days in the P and the F arms, respectively. Conclusions: Our findings suggest that Pegfilgrastim, at least as efficient and safe than Filgrastim on clinical outcomes, strictly dominates Filgrastim in terms of economic outcomes, i.e. had better effectiveness and lower costs, on most common intermediate efficacy criteria. Therefore, Pegfilgrastim should be considered as a standard of care in patients with lymphoma and myeloma after high-dose chemotherapy and autologous stem cell transplantation. This study was partly supported by Amgen France S.A.S. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Busulfan systemic exposure and its relationship with efficacy and safety in hematopoietic stem cell transplantation in children: A meta-analysis

2020 ◽  
Author(s):  
Xinying Feng ◽  
Yunjiao Wu ◽  
Jingru Zhang ◽  
Jiapeng Li ◽  
Guanghua Zhu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Failure ◽  
Systemic Exposure ◽  
Time Curve ◽  
Hematopoietic Stem ◽  
Concentration Time ◽  
The Mean

Abstract Background: Busulfan (Bu) is a key component of several conditioning regimens used before hematopoietic stem cell transplantation (HSCT). However, the optimum systemic exposure (expressed as the area under the concentration-time curve [AUC]) of Bu for clinical outcome in children is controversial. Methods: Research on pertinent literature was carried out at PubMed, EMBASE, ClinicalTrials.gov and the Cochrane Library. Observational studies were included, which compared clinical outcomes above and below the area under the concentration-time curve (AUC) cut-off value, which we set as 800, 900, 1000, 1125, 1350, and 1500 µM × min. The primary efficacy outcome was notable in the rate of graft failure. In the safety outcomes, incidents of veno-occlusive disease (VOD) were recorded, as well as other adverse events. Results: Thirteen studies involving 548 pediatric patients (aged 0.3-18 years) were included. Pooled results showed that, compared with the mean Bu AUC (i.e., the average value of AUC measured multiple times for each patient) of > 900 µM × min, the mean AUC value of <900 µM × min significantly increased the incidence of graft failure (RR=3.666, 95% CI:1.419, 9.467). The incidence of VOD was significantly decreased with the mean AUC <1350 µM × min (RR=0.370, 95% CI: 0.205-0.666) and <1500 µM × min (RR=0.409, 95% CI: 0182-0.920). Conclusions: In children, Bu mean AUC above the cut-off value of 900 µM × min (after every 6-hour dosing) was associated with decreased rates of graft failure, while the cut-off value of 1350 µM × min were associated with increased risk of VOD in children, particularly for the patients without VOD prophylaxis therapy. Further well-designed prospective and multi centric randomized controlled trials with larger sample size are necessary before putting our result into clinical practices.

scholarly journals Busulfan systemic exposure and its relationship with efficacy and safety in hematopoietic stem cell transplantation in children: A Meta-Analysis

2019 ◽  
Author(s):  
Xinying Feng ◽  
Libo Zhao ◽  
Yunjiao Wu ◽  
Jingru Zhang ◽  
Jiapeng Li ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Failure ◽  
Systemic Exposure ◽  
Time Curve ◽  
Hematopoietic Stem ◽  
Concentration Time ◽  
The Mean

Abstract Background Busulfan (Bu) is a key component of several conditioning regimens used before hematopoietic stem cell transplantation (HSCT). However,the optimum systemic exposure (expressed as the area under the concentration-time curve [AUC]) of Bu for clinical outcome in children is controversial. Methods Research on pertinent literature was carried out at PubMed, EMBASE, ClinicalTrials.gov and the Cochrane Library. Observational studies were included, which compared clinical outcomes above and below the area under the concentration-time curve (AUC) cut-off value, which we set as 800, 900, 1000, 1125, 1350, and 1500 µM × min. The primary efficacy outcome was notable in the rate of graft failure. In the safety outcomes, incidents of veno-occlusive disease (VOD) were recorded, as well as other adverse events. Results Thirteen studies involving 548 pediatric patients (aged 0.3-18 years) were included. Pooled results showed that, compared with the mean Bu AUC (i.e., the average value of AUC measured multiple times for each patient) of > 900 µM × min, the mean AUC value of <900 µM × min significantly increased the incidence of graft failure (RR=3.049, 95% CI: 1.285-7.234). The incidence of VOD was significantly decreased with the mean AUC <1350 µM × min (RR=0.370, 95% CI: 0.205-0.666) and <1500 µM × min(RR=0.409, 95% CI: 0182-0.920). Conclusions In children, Bu the mean AUC of 900 µM × min should be considered the lowest threshold associated with its effective prevention of graft failure, while the mean AUC of >1350 µM × min is associated with increased VOD, particularly for the patients not undergoing VOD prophylaxis therapy.

Once Daily IV Busulfan Given with Fludarabine in Allogeneic Stem Cell Transplantation Conditioning: High vs Low Busulfan AUC Does Not Alter Toxicities or Transplant Outcome.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1763-1763
Author(s):  
Michelle Geddes ◽  
Shabal B. Kangarloo ◽  
Farrukh Naveed ◽  
Ahsan M. Chaudhry ◽  
Oluyemi Jeje ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Drug Exposure ◽  
Once Daily ◽  
Concentration Time ◽  
Systemic Drug Exposure ◽  
Grade Ii ◽  
Treatment Related Mortality ◽  
Systemic Drug ◽  
Related Mortality

Abstract Background: Busulfan (Bu), a bifunctional alkylating agent used in conditioning regimens for allogeneic hematopoietic stem cell transplantation (HSCT), has unpredictable oral intestinal absorption. Subsequent marked variability in systemic drug exposure increases the risk of relapsed leukemia or graft failure in patients with a low area under the plasma concentration-time curve (AUC), and for toxicities with a high AUC. Purpose: To assess once daily intravenous (IV) busulfan for interpatient variability in AUC, transplant outcomes and toxicities in patients with high and low systemic busulfan exposures, and to evaluate therapeutic AUC. Methods: 68 patients ages 19–63 with hematologic malignancies received once daily IV Bu (Busulfex, ESP Pharma) between July 2000 and August 2004 at a myeloablative dose of 3.2 mg/m2 on days −5 to −2 and fludarabine 50mg/m2 on days −6 to −2 inclusive prior to HSCT. Additional TBI 200cGy x 2 was given to 24 patients with acute leukemia. Graft-vs-host disease (GVHD) prophylaxis for all pts comprised cyclosporine A, short course methotrexate with folinic acid and antithymocyte globulin in divided doses over 3 consecutive days pretransplant finishing day 0. Busulfan concentrations in plasma were determined by UV-HPLC. All concentration-time plasma Bu data were analyzed by non-compartmental analysis using WinNonlin Version 4.1 software (Pharsight Corporation, Mountain View, CA, USA). Results: The range of AUC was 2184 to 7513 μ M.min (med 4822 μ M.min). Patients were analyzed in 2 groups of 34 patients with exposures below (L) or above (H) the median AUC and followed for 12–61 months (med 26). Groups consisted of diverse malignancies with no difference in median age (L 46y, H 43y), number of unrelated or mismatched related donors (L 32%, H 38%), standard-risk leukemias (L 32%, H 29%), and TBI (L 41%, H 32%). Median days of engraftment for platelets &gt;20 (19d) and neutrophils &gt;0.5 (16d) were identical. There was no significant difference between the low or high AUC groups in 3y projected OS (L 69±8% vs H 67±8%), treatment-related mortality (TRM, L 16±7% vs H 21±7%), median months progression-free survival (L 17, H 19), venoocclusive disease (L 0%, H 6%), stomatitis ≥ grade II (L 82%, H 97%), hemmorhagic cystitis (L 15%, H 18%), acute GVHD grade III–IV (L 6%, H 18%), or grade II liver toxicity (L 12%, H 3%). Rate of relapse did not differ between groups (L 29%, H 24%). One patient in the high AUC group with subtherapeutic dilantin levels had a seizure. There was a trend to increased TRM with death in 3 of 8 patients (38%) with an AUC &gt;6000 μ M.min, compared to 10 of 60 patients (17%) with AUC &lt;6000 μ M.min (p=0.09). Conclusions: Although once daily IV Bu dosing provides a more predictable AUC than oral dosing, there remains 3–4 fold variability in systemic drug exposure. In this heterogeneous group of patients, differences in AUC within this range had little impact on survival, treatment related mortality or significant toxicities. This data suggests targeting AUC around 5000–6000 μ M.min with or without TBI is feasible and that although more data is required to assess the whether high exposures (&gt;6000 μ M.min) increase risk, in general dosing without PK monitoring is safe.

Lenalidomide after Allogeneic Stem Cell Transplantation in Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4840-4840 ◽  
Author(s):  
Friederike Lehmann ◽  
El-Cheikh Jean ◽  
Tatjana Zabelina ◽  
Francis Ayuk ◽  
Christine Wolschke ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Dose Reduction ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Hematological Toxicity ◽  
High Dose ◽  
Once Daily ◽  
Grade 3

Abstract Background: Lenalidomide is an immunmodulatory drug, orally administered once daily, which is effective in relapsed multiple myeloma (MM). Here, we evaluated the efficacy and toxicity of lenalidomide in 16 MM patients with relapsed disease after allogeneic stem cell transplantation (allo-SCT). Methods: Median age was 57 (range 37–68) years. The series included 5 females and 11 males. Prior to allo-SCT, all patients were heavily pretreated with multiple lines of chemotherapy, including high dose therapy with autologous stem cell support. Also, prior to lenalidomide treatment, other salvage therapies included donor lymphocyte infusions (DLI) in 93% of cases, thalidomide in 63%, and bortezomib in 88%. NCI-criteria were used to define toxicity. Lenalidomide was given 25 mg orally once daily on day 1–21 every 28 days. No prophylactic anticoagulation was used. Results: The overall median number of completed cycles was 5 (range 1–10). Very good partial response (VGPR) was achieved in 13%, partial remission (PR) in 53%, and stable disease (SD) in 27% of the patients. During the follow up period, disease progression was observed in 50% of cases, and death in one patient. The median progression-free survival was 8 months, while the median overall survival was not yet reached. Hematotoxicity was the primarily and major encountered side effect (leukopenia: 6% grade 4, 19% grade 3, 19% grade 2, 38% grade 1; thrombopenia: 19% grade 3, 19% grade 2, 31% grade 1). This myelotoxicity led to dose reduction (usually 10 mg) in 44% of the patients. Infectious complications were observed in 25%. Non-hematological toxicity was also seen in 75% of cases (56% grade 1, 19% grade 2), consisting of cramps in the leg, constipation, symptomatic fatigue, nausea and progressing polyneuropathy (n=1). Thrombembolic complications (cerebral infarction) were observed only in one patient, who was receiving concomitant corticosteroid treatment for acute graft-versus-host disease (GvHD), but neurological symptoms resolved completely. GvHD of the skin under lenalidomide treatment was seen in 25% of cases (one grade 2, and 3 grades 1), with one case occurring shortly after an additional DLI. Conclusions: Lenalidomide is effective in relapsed patients with MM after allo-SCT. Major toxicity is myelotoxicity, which required dose reduction in a majority of patients. With this background, a dose-finding study to determine the optimal lenalidomide dose as maintenance therapy after allo-SCT has already started.

A Phase 2 Study of Bortezomib in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4746-4746 ◽  
Author(s):  
Sven de Vos ◽  
Donna Fernando ◽  
David P. Schenkein ◽  
Peter J. Rosen
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Lymphoma ◽  
Single Agent ◽  
High Dose Chemotherapy ◽  
Clinical Activity ◽  
High Dose ◽  
Phase 2 ◽  
Heavily Pretreated ◽  
The Mean

Abstract The novel proteasome inhibitor bortezomib (Velcade®) is approved for the treatment of multiple myeloma following at least one prior therapy. Recently, bortezomib was shown to be active in relapsed mantle cell lymphoma and some low grade B-cell non-Hodgkin’s lymphomas. We conducted a phase 2 trial to evaluate the overall response rate (ORR) following treatment with single agent bortezomib in patients with relapsed DLBCL. Non-hospitalized patients with measurable disease, and a Karnofsky Performance Score > 60%, were eligible for the trial if they had relapsed after or were refractory to their most recent chemotherapy. Patients had to be either not eligible for high dose chemotherapy with stem cell support or had already received a stem cell transplantation. The treatment schedule was: bortezomib 1.3 mg/m2 via intravenous bolus on days 1, 4, 8, and 11 of a 21-day cycle for up to 8 cycles. Responses were assessed using the International Workshop criteria (J Clin Oncol. 1999;17:1244). Ten patients were enrolled in this trial with one screen failure. The mean age was 60 years (range 22 to 83). The study population was heavily pretreated with a mean of 4.6 (range 2 to 7) prior chemotherapy regimens. Three patients (33.3 %) had received high dose chemotherapy with stem cell transplantation. The mean number of treatment cycles received was 2.33 (range 1 to 8). One of nine patients had stable disease (SD) and completed all 8 treatment cycles whereas all other patients progressed while on study drug (PD). The treatment was well tolerated. Grade ≥ 3 AEs included thrombocytopenia, neutropenia, hyponatremia, and hyperkalemia. In summary, single agent bortezomib is not an active drug in heavily pretreated patients with relapsed/refractory DLBCL. Bortezomib has clinical activity as single agent in other lymphoma subtypes and there is at least additive preclinical and clinical activity in combination with other agents. Therefore, investigation of bortezomib-containing combination therapies might be considered in less heavily pretreated DLBCL patients.

scholarly journals Busulfan systemic exposure and its relationship with efficacy and safety in hematopoietic stem cell transplantation in children: A meta-analysis

2020 ◽  
Author(s):  
Xinying Feng ◽  
Yunjiao Wu ◽  
Jingru Zhang ◽  
Jiapeng Li ◽  
Guanghua Zhu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Failure ◽  
Systemic Exposure ◽  
Time Curve ◽  
Hematopoietic Stem ◽  
Concentration Time ◽  
The Mean

Abstract Background: Busulfan (Bu) is a key component of several conditioning regimens used before hematopoietic stem cell transplantation (HSCT). However, the optimum systemic exposure (expressed as the area under the concentration-time curve [AUC]) of Bu for clinical outcome in children is controversial. Methods: Research on pertinent literature was carried out at PubMed, EMBASE, ClinicalTrials.gov and the Cochrane Library. Observational studies were included, which compared clinical outcomes above and below the area under the concentration-time curve (AUC) cut-off value, which we set as 800, 900, 1000, 1125, 1350, and 1500 µM × min. The primary efficacy outcome was notable in the rate of graft failure. In the safety outcomes, incidents of veno-occlusive disease (VOD) were recorded, as well as other adverse events. Results: Thirteen studies involving 548 pediatric patients (aged 0.3-18 years) were included. Pooled results showed that, compared with the mean Bu AUC (i.e., the average value of AUC measured multiple times for each patient) of > 900 µM × min, the mean AUC value of <900 µM × min significantly increased the incidence of graft failure (RR=3.666, 95% CI:1.419, 9.467). The incidence of VOD was significantly decreased with the mean AUC <1350 µM × min (RR=0.370, 95% CI: 0.205-0.666) and <1500 µM × min (RR=0.409, 95% CI: 0182-0.920). Conclusions: In children, Bu mean AUC above the cut-off value of 900 µM × min (after every 6-hour dosing) was associated with decreased rates of graft failure, while the cut-off value of 1350 µM × min were associated with increased risk of VOD in children, particularly for the patients without VOD prophylaxis therapy. Further well-designed prospective and multi centric randomized controlled trials with larger sample size are necessary before putting our result into clinical practices.

scholarly journals Busulfan systemic exposure and its relationship with efficacy and safety in hematopoietic stem cell transplantation in children: A Meta-Analysis

2020 ◽  
Author(s):  
Xinying Feng ◽  
Yunjiao Wu ◽  
Jingru Zhang ◽  
Jiapeng Li ◽  
Guanghua Zhu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Failure ◽  
Systemic Exposure ◽  
Time Curve ◽  
Hematopoietic Stem ◽  
Concentration Time ◽  
The Mean

Abstract Background : Busulfan (Bu) is a key component of several conditioning regimens used before hematopoietic stem cell transplantation (HSCT). However, the optimum systemic exposure (expressed as the area under the concentration-time curve [AUC]) of Bu for clinical outcome in children is controversial. Methods : Research on pertinent literature was carried out at PubMed, EMBASE, ClinicalTrials.gov and the Cochrane Library. Observational studies were included, which compared clinical outcomes above and below the area under the concentration-time curve (AUC) cut-off value, which we set as 800, 900, 1000, 1125, 1350, and 1500 µM × min. The primary efficacy outcome was notable in the rate of graft failure. In the safety outcomes, incidents of veno-occlusive disease (VOD) were recorded, as well as other adverse events. Results : Thirteen studies involving 548 pediatric patients (aged 0.3-18 years) were included. Pooled results showed that, compared with the mean Bu AUC (i.e., the average value of AUC measured multiple times for each patient) of > 900 µM × min, the mean AUC value of <900 µM × min significantly increased the incidence of graft failure (RR=3.049, 95% CI: 1.285-7.234). The incidence of VOD was significantly decreased with the mean AUC <1350 µM × min (RR=0.370, 95% CI: 0.205-0.666) and <1500 µM × min (RR=0.409, 95% CI: 0182-0.920). Conclusions : In children, Bu mean AUC above the cut-off value of 900 µM × min (after every 6-hour dosing) was associated with decreased rates of graft failure, while the cut-off value of 1350 µM × min were associated with increased risk of VOD in children, particularly for the patients without VOD prophylaxis therapy. Further well-designed prospective and multi centric randomized controlled trials with larger sample size are necessary before putting our result into clinical practices.

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