melphalan and Genetic-Diseases--Inborn

We conducted a phase I/II trial, to evaluate the efficacy and safety of an intravenous liposomal formulation of busulphan (LBu) as a myeloablative agent for stem cell transplantation (SCT). The liposomal busulphan was administered as a 3 h infusion twice daily over 4 consecutive days. Six adults received 1.6-2 mg/kg/dose and 18 children received 1.8-3 mg/kg/dose. Pharmacokinetic parameters were studied after the first and the last dose of busulphan. No significant difference in clearance, AUC, elimination half-lives or distribution volume between the first and the last dose was found in either groups. A significantly (P < 0.005) higher clearance was observed in children after the first and the last dose (3.61 and 3.79 ml/min/kg, respectively) compared to adults (2.40 and 2.33 ml/min/kg, respectively). The elimination half-lives after the first and the last dose were significantly (P < 0.005) shorter in children (2.59 and 2.72 h, respectively) compared to adults (3.35 and 3.61 h, respectively). Clearance correlated significantly with age. However, no significant correlation with age was observed when clearance was adjusted to the body surface area. Two cases of VOD following a total dose of 24 mg/kg were observed. Six patients experienced mucositis. No other organ toxicity was observed. We conclude that intravenous liposomal busulphan pharmacokinetics is age dependent. A dosage schedule based on body surface area should be used especially in young children to reduce the age-dependent difference in kinetics. An intravenous liposomal dose of busulphan of 500 mg/m(2) is suggested to reach a similar systemic exposure and myeloablative effect in both children and adults. Moreover, the novel liposomal form of busulphan showed a favorable toxicity profile and seems safe as a part of the high-dose therapy prior to SCT.

Topics: Adult; Age Factors; Busulfan; Child; Cyclophosphamide; Drug Administration Schedule; Drug Carriers; Female; Genetic Diseases, Inborn; Graft vs Host Disease; Half-Life; Hematologic Neoplasms; Hepatic Veno-Occlusive Disease; Humans; Immunosuppressive Agents; Infant; Infusions, Intravenous; Liposomes; Male; Melphalan; Metabolic Clearance Rate; Middle Aged; Peripheral Blood Stem Cell Transplantation; Stomatitis; Transplantation Conditioning

Immune reconstitution appears to be delayed following myeloablative conditioning (MAC) and umbilical cord blood transplantation (UCBT) in paediatric recipients. Although reduced toxicity conditioning (RTC) versus MAC prior to allogeneic stem cell transplantation is associated with decreased transplant-related mortality, the effects of RTC versus MAC prior to UCBT on immune reconstitution and risk of graft-versus-host disease (GVHD) are unknown. In 88 consecutive paediatric recipients of UCBT, we assessed immune cell recovery and immunoglobulin reconstitution at days +100, 180 and 365 and analysed risk factors associated with acute and chronic GVHD. Immune cell subset recovery, immunoglobulin reconstitution, and the incidence of opportunistic infections did not differ significantly between MAC versus RTC groups. In a Cox model, MAC versus RTC recipients had significantly higher risk of grade II-IV acute GVHD [Hazard Ratio (HR) 6·1, P = 0·002] as did recipients of 4/6 vs. 5-6/6 HLA-matched UCBT (HR 3·1, P = 0·03), who also had significantly increased risk of chronic GVHD (HR 18·5, P = 0·04). In multivariate analyses, MAC versus RTC was furthermore associated with significantly increased transplant-related (Odds Ratio 26·8, P = 0·008) and overall mortality (HR = 4·1, P = 0·0001). The use of adoptive cellular immunotherapy to accelerate immune reconstitution and prevent and treat opportunistic infections and malignant relapse following UCBT warrants further investigation.

Topics: Alemtuzumab; Antibiotic Prophylaxis; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antilymphocyte Serum; Busulfan; Child; Child, Preschool; Cord Blood Stem Cell Transplantation; Cyclophosphamide; Female; Genetic Diseases, Inborn; Graft Survival; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leukocyte Count; Male; Melphalan; Myeloablative Agonists; Neoplasms; Neutrophils; Recombinant Proteins; Retrospective Studies; T-Lymphocytes; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Whole-Body Irradiation

Topics: Antifungal Agents; Antilymphocyte Serum; Antineoplastic Agents; Aspergillosis, Allergic Bronchopulmonary; Base Sequence; Bone Marrow Transplantation; DNA, Mitochondrial; Electron Transport; Female; Genetic Diseases, Inborn; Graft vs Host Disease; Humans; Immunosuppressive Agents; Infant; Leukemia, Myeloid; Melphalan; Mitochondrial Diseases; Myeloablative Agonists; Sequence Deletion; Syndrome; Transplantation Conditioning; Transplantation, Homologous; Treatment Failure; Vidarabine

In order to control busulfan pharmacokinetic variability and toxicity, a specific monitoring protocol was instituted in our bone marrow transplant BMT paediatric patients including a test dose, daily Bayesian forecasting of busulfan plasma levels, and Bayesian individualization of busulfan dosage regimens. Twenty-nine children received BMT after a busulfan-based conditioning regimen. Individual pharmacokinetic parameters were obtained following a 0.5 mg*kg test dose and were used for daily individualization of dosage regimens during the subsequent 4-day course of treatment. Doses were adjusted to reach a target mean AUC per 6 h between 4 and 6 microg.h.ml(+1). Plasma busulfan assays were performed by liquid chromatography. Pharmacokinetic analysis used the USC*PACK software. The performance of the test dose to predict AUC during the busulfan regimen was evaluated. Incidence of toxicity, chimerism and relapse, overall Kaplan-Meier survival, and VOD-free survival were compared after matching our patients (group A) with patients conditioned by using standard doses of busulfan (group B). Busulfan doses were decreased in 69% of patients compared to conventional doses. Expected AUC was significantly correlated with observed AUC and predictability of the test dose was 101.9 +/- 17.9%. Incidence of VOD in group A was 3.4% vs 24.1% in group B, while the incidence of stomatitis was similar. Engraftment was successful in all patients in group A. The rate of full engraftment at 3 months post-BMT was higher in group A (P = 0.012). Long-term overall survival did not differ between the two groups, in contrast to the 90-day survival. VOD-free survival was higher in group A (P = 0.026). Pharmacokinetic monitoring and individualization of busulfan dosage regimen are useful in improving clinical outcome and reducing early mortality in paediatric bone marrow transplant recipients.

Topics: Adolescent; Alkylating Agents; Area Under Curve; Bayes Theorem; Bone Marrow Transplantation; Busulfan; Child; Child, Preschool; Cyclophosphamide; Etoposide; Female; Genetic Diseases, Inborn; Graft Survival; Hematologic Neoplasms; Hepatic Veno-Occlusive Disease; Humans; Incidence; Infant; Life Tables; Male; Melphalan; Prospective Studies; Severe Combined Immunodeficiency; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome