Fixed-dose administration and pharmacokinetically guided adjustment of busulfan dose for patients undergoing hematopoietic stem cell transplantation: a meta-analysis and cost-effectiveness analysis.

This study aims to evaluate the efficacy, safety, and long-term cost-effectiveness of fixed-dose busulfan (Bu) administration and pharmacokinetically (PK) guided adjustment of Bu dose for patients who underwent hematopoietic stem cell transplantation. The efficacy and safety of both dosing strategies were compared using a systematic review and meta-analysis. A Markov model was used in estimating relevant cost and health outcomes from the perspective of the health system. The primary outcomes of interest were lifetime cost, quality adjusted life-years (QALYs) gained, and incremental cost-effectiveness ratio (ICER) in dollar per QALY gained. Results showed that progression-free survival and overall survival in the PK-guided group were higher than that in the fixed-dose group, and the PK-guided group was associated with low non-relapse mortality and relapse rate. In contrast to safety, the incidence of acute graft-versus-host disease (GVHD) was the same in the two groups (P > 0.05). Cost-effectiveness analysis showed that the QALY of the PK-guided group (12.8135 QALYs and $582,475.07) increased by 2.0609 relative to that in the fixed-dose group (10.7526 QALYs and $562,833.20), and the ICER was $9530.72/QALY. One-way and probability sensitivity analyses confirmed the reliability of the results. In conclusion, the PK-guided approach has higher efficacy and is safer.

Costs and Outcomes with Once-Daily versus Every-6-Hour Intravenous Busulfan in Allogeneic Hematopoietic Cell Transplantation.

The high cost of healthcare in the United States has not been consistently associated with improved health outcomes or quality of care, necessitating a focus on value-based care. We identified busulfan dosing frequency during allogeneic hematopoietic cell transplantation (HCT) conditioning as a potential target for optimization. To improve patient convenience and to decrease the cost of busulfan-based conditioning regimens, our institution changed busulfan dose frequency from every 6 hours (q6h) to once-daily (q24h). We compared costs and patient outcomes between these 2 dosing schedules. In June 2017, our institution transitioned from q6h to q24h busulfan dosing. We compared patients who received busulfan/cyclophosphamide conditioning regimens (BU/CY) for allogeneic HCT in the year before the dosing change (q6h cohort) and those who did so in the year after the dosing change (q24h cohort). The primary outcomes were differences in cost, day +90 mortality, and day +90 relapse. Between June 1, 2016, and June 1, 2018, 104 patients (median age 49 years; range, 20 to 63 years) received BU/CY before allogeneic HCT. Fifty-nine patients (57%) received q6h busulfan and 45 (43%) received q24h busulfan. There were fewer men in the q24h busulfan cohort compared with the q6h busulfan cohort (42% versus 64%; P = .024), but there were no other significant differences between the groups. There was an average annual cost savings of $19,990 per patient with q24h busulfan compared with q6h busulfan, and an annual busulfan cost savings of $899,550. There was a significantly lower day +90 mortality in the q24h busulfan cohort compared to the q6h busulfan cohort (0% versus 10%; P = .028). There were no significant differences in relapse at day +90 or in hospital length of stay. Our data indicate that i.v. busulfan dosing for allogeneic HCT conditioning is a target for improved value-based care. At our institution, patients who received q24h busulfan dosing had similar or superior outcomes compared with those receiving q6h dosing, with an average annual cost reduction of $19,990 per patient and an overall annual reduction in busulfan cost of approximately $900,000. These data support the adoption of q24h i.v. busulfan dosing as a standard of care to improve value-based care in allogeneic HCT.

Economic and clinical aspects of intravenous versus oral busulfan in adult patients for conditioning prior to HSCT.

PURPOSE: Busulfan (BU) used as cytoreductive conditioning prior to hematopoietic stem cell transplantation (HSCT) is available as intravenous (IV) and oral (O) preparation. IV-BU has clinical advantages associated with relevant incremental costs. The aim was to determine the economic impact of IV-BU versus O-BU in adult HSCT recipients from a German health care providers' perspective. METHODS: A budget-impact model (BIM) including costs and risks for oral mucositis (OM), infection with OM, and hepatic sinusoidal obstruction syndrome (SOS) was developed. Model inputs are literature data comparing clinical effects of IV-BU versus O-BU and German cost data (conditioning therapy, treatment of OM, infections, SOS without/with multiorgan failure) from literature and tariff lists. RESULTS: Base case calculations resulted the following: total costs of adverse events were €86,434 with O-BU and €44,376 with IV-BU for ten patients each. Considering costs of adverse events and drugs, about €5840 for ten patients receiving IV-BU are saved. Sensitivity analyses were conducted in several ways. Cost savings range between €4910 and €12,640 per ten patients for all adverse events and €2070 or €1140 per ten patients considering SOS only. Drug treatment of SOS and treatment of multiorgan failure during severe SOS are major cost drivers. Worst case scenario calculations (assuming -25% risk of all adverse events for O-BU and +25% for IV-BU) yield up to €27,570 per ten patients with IV-BU. CONCLUSIONS: Considering costs of adverse events and drugs, IV-BU is the dominant alternative from a German providers' perspective. For more comprehensive economic evaluations, additional epidemiological data, evidence on clinical outcomes, patient-reported outcomes, and treatment patterns are needed.

The modification of high-dose therapy shortens the duration of neutropaenia by delay of leucocyte nadir.

Infections during neutropaenia contribute still significantly to mortality and morbidity after high-dose therapy and autologous stem cell transplantation. Further acceleration of haemopoietic recovery seems impossible for biological reasons. Another approach to shorten neutropaenia could be to remove drugs from high-dose therapy protocols with strong contribution to immunosuppression and neutropaenia and unproven antineoplastic activity. In this retrospective matched-pair analysis, conventional busulphan/cyclophosphamide (Bu/Cy) high-dose therapy was compared to single-agent busulphan conditioning before autologous stem cell transplantation. This modification led to a significant shorter neutropaenic interval by protraction of cell decrease and to a significant mitigation of neutropaenia. After single-agent busulphan conditioning, leucocytes dropped below 1/nl at median 1.5 days later when compared to the patients from the busulphanBu/Cy control group (P=0.001). In a significant percentage of patients (n=6, 60%) leucocytes did not fall below 0.5 cells/nl at any time. In contrast, all patients from the Bu/Cy control group experienced deep neutropaenia (P=0.004). Thrombocytopaenia and requirement for transfusions of platelets or red cells were not influenced. Antineoplastic activity seemed to be preserved as determined by survival analysis. In conclusion, modification of high-dose regimen with the intention to shorten neutropaenia with preserved antitumour activity could be an approach to reduce infection-related morbidity and mortality and to consider economic necessities.