Busulfan and cyclophosphamide (BuCy) is a frequently used myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT). Theoretical considerations and pharmacological data indicate that application of busulfan prior to subsequent cyclophosphamide (BuCy) may trigger liver toxicity. Reversing the order of application to cyclophosphamide-busulfan (CyBu) might be preferable, a hypothesis supported by animal data and retrospective studies. We performed a prospective randomized trial to determine impact of order of application of Bu and Cy before allo-HCT in 70 patients with hematological malignancy, 33 patients received BuCy and 37 CyBu for conditioning. In the short term, there were minimal differences in liver toxicity favoring CyBu over BuCy, significant only for alanine amino transferase at day 30 (p = 0.03). With longer follow-up at 4 years, non-relapse mortality (6% versus 27%, p = 0.05) was lower and survival (63% versus 43%, p = 0.06) was higher with CyBu compared to BuCy. Other outcomes, such as engraftment (p = 0.21), acute and chronic graft-versus-host disease (p = 0.40; 0.36), and relapse (p = 0.79), were similar in both groups. We prospectively show evidence that the order of application of Cy and Bu in myeloablative conditioning in allo-HCT patients has impact on outcome.

Busulfan (Bu) is widely used in conditioning regimens before allogeneic hematopoietic cell transplantation, with variable metabolism due to interindividual differences of pharmacokinetics (PK). The purpose of this study was to correlate pharmacokinetics and clinical outcomes. Lower-AUC, in range-AUC and higher-AUC were defined as ±25% of the targeted Bu-AUC. In 2019, we changed Bu dosing from 4×/day (Bu-4) to 1×/day (Bu-1) for ease of application. AUC-target range was reached in 46% of patients; 40% were in low-AUC and 14% in high-AUC. Among all toxicities, viral and fungal infections were significantly more frequent in high-AUC compared with low-AUC (20% vs. 8%; p = 0.01 and 37% vs. 17%; p = 0.03). Bu-1 showed lower PK values (66% vs. 36% of Bu-4 in low-AUC; p < 0.01) and higher incidence of mucositis (p = 0.02). Long-term outcomes at 2 years showed a higher non-relapse mortality (NRM) (p < 0.01) and higher relative risk of death in the high-AUC group compared to the other groups. Cumulative incidence of relapse and acute/chronic GvHD were not significantly different. The optimal cut-off in Bu-AUC associated with low NRM was 969 µmol/l*min (ROC AUC 0.67, sensitivity 0.86 and specificity 0.47) for Bu-4. In conclusion, low-AUC BU-PK seems of benefit regarding NRM and survival.

Busulfan (Bu) combined with cyclophosphamide (Cy) is commonly used as a myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT). There is inter-individual variability of Bu pharmacokinetics (PK) and hence in toxicity and efficacy. The introduction of therapeutic drug monitoring (TDM) of Bu has decreased toxicity of the regimen. Hepatic metabolism of Bu is mediated through Glutathione-S-Transferases (GSTs), mainly GSTA1. Patients with GSTA1*A variants are considered normal metabolizers and GSTA1*B corresponds to poor metabolism, defined by nucleotide changes at −52 or −69 locus in GSTA1 promoter region. The aim of the study was to explore the correlation between GSTA1 polymorphisms and Bu-PK in 60 adult patients receiving an allo-HCT in the BuCyBu clinical study (ClinicalTrials.gov I, ID NCT01779882) comparing the sequence BuCy to CyBu. DNA samples prior to conditioning were genotyped for candidate variants at −52 (rs3957356) and −69 (rs3957357) loci in the GSTA1 promoter. Thirty-three % of patients were GSTA1*A*A, 49% GSTA1*A*B and 18% GSTA1*B*B. In GSTA1*A*A patients, median Bu-AUC was 3.6 ± 0.7 mg*h/L, in GSTA1*A*B 4.5 ± 1.6 and in GSTA1*B*B 4.9 ± 1.4 (AUC 35% higher than GSTA1*A*A, p = 0.03), with a similar significant correlation with Bu-clearance (p = 0.04). The correlation between GSTA1 polymorphism and AUC remained significant in multivariate linear regression analysis. There was a trend for lower non-relapse mortality (NRM) in patients with low AUC. We could not demonstrate a correlation between GSTA1 polymorphisms and NRM, acute graft-versus-host disease (aGvHD) in this small cohort, but there is a trend of higher aGvHD incidence in GSTA1*B*B patients.

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Pacing-induced cardiomyopathy (PICM) consists of heart failure (HF) associated with a drop in the left ventricular ejection fraction (LVEF) in the setting of high-burden right ventricular pacing, with presentation that may range from subclinical to severe. Time to manifestation can go from weeks to years after device implantation. Treatment typically consists in an upgrade to a cardiac resynchronisation therapy (CRT) or His bundle pacing (HisP). Several risk factors for PICM have been described and should be considered before pacemaker (PM) implantation, as thorough patient selection for de novo CRT or HisP, may preclude its manifestation. We present the case of an 82-year-old patient presenting with acute congestive HF and new severely reduced LVEF, 30 days following dual chamber PM implantation for high-grade atrioventricular block. Treatment with HF medication and upgrade to a CRT permitted rapid resolution of the symptoms and normalisation of the LVEF at 1-month follow-up.