Dose individualization of intravenous busulfan in pediatric patients undergoing bone marrow transplantation: impact and in vitro evaluation of infusion lag-time.

OBJECTIVES: To apply therapeutic drug monitoring and dose-individualization of intravenous Busulfan to paediatric patients and evaluate the impact of syringe-pump induced Busulfan infusion lag-time after in vitro estimation. METHODS: 76 children and adolescents were administered 2 h intravenous Busulfan infusion every 6 h (16 doses). Busulfan plasma levels, withdrawn by an optimized sampling scheme and measured by a validated HPLC-PDA method, were used to estimate basic PK parameters, AUC, Cmax, kel, t1/2, applying Non-Compartmental Analysis. In vivo infusion lag-time was simulated in vitro and used to evaluate its impact on AUC estimation. KEY FINDINGS: Mean (%CV) Busulfan AUC, Cmax, clearance and t1/2 for pediatric population were found 962.3 µm × min (33.1), 0.95 mg/L (41.4), 0.27 L/h/kg (33.3), 2.2 h (27.8), respectively. TDM applied to 76 children revealed 6 (7.9%) being above and 25 (32.9%) below therapeutic-range (AUC: 900-1350 µm × min). After dose correction, all patients were measured below toxic levels (AUC < 1500 µm × min), no patient below 900 µm × min. Incorporation of infusion lag-time revealed lower AUCs with 17.1% more patients and 23.1% more younger patients, with body weight <16 kg, being below the therapeutic-range. CONCLUSIONS: TDM, applied successfully to 76 children, confirmed the need for Busulfan dose-individualization in paediatric patients. Infusion lag-time was proved clinically significant for younger, low body-weight patients and those close to the lower therapeutic-range limit.

Long-term immunity to measles, mumps and rubella after MMR vaccination among children with bone marrow transplants.

Measles, mumps and rubella (MMR) vaccine-induced long-term immunity was studied in 30 children with bone marrow transplants (BMT). Immunity at baseline for MMR was 13.3, 33.3 and 66.6%, respectively. MMR vaccination failed to induce adequate and persistent responses to measles and mumps; seropositivity at 1 and 12 months for measles was 26.6 and 23.3% and for mumps 46.6 and 36.6%, respectively. In contrast, 27 of 30 children with a BMT were immune to rubella 1 month after immunization and retained protective antibody levels at 12 months. The MMR-induced anamnestic responses to rubella among all responders were associated with the production of high avidity antibodies. We conclude that a single dose of MMR given at 2 years after BMT induces suboptimal and short-lived immune responses to measles and mumps; a second dose should be recommended for paediatric BMT recipients.

The oral manifestations of chronic graft-versus-host disease (cGVHD) in paediatric allogeneic bone marrow transplant recipients.

The oral manifestations of chronic graft-versus-host disease (cGVHD) in eight allogeneic bone marrow transplant (BMT) paediatric recipients were studied clinically, and lip biopsies were performed in seven of them. A prominent lichenoid reaction was observed in four patients, two with accompanying ulceration. Superficial mucoceles were present in three children. Clinically obvious xerostomia was seen in seven patients. Lip biopsies were positive and correlated with the clinical manifestations. Both clinical and histological findings confirmed the diagnosis of cGVHD. In three additional children, with systemic manifestations indicating cGVHD, the oral mucosa was clinically and histologically normal, and the systemic manifestations were, thus, attributed to drug reactions. The above findings indicate the high value of oral examination in diagnosing or confirming paediatric cGVHD. Superficial mucoceles, reported for the first time in paediatric recipients, seem to be important in the early diagnosis of cGVHD.

Kinetics of antibody concentration and avidity for the assessment of immune response to pneumococcal vaccine among children with bone marrow transplants.

The kinetics of the immune response to the 23-valent pneumococcal polysaccharide vaccine (PPV) were studied in 38 children who received bone marrow transplants (BMTs). Anti-pneumococcal antibody concentrations increased 1 and 3 months after vaccination for all 5 serotypes tested, but, in 21 children, the vaccine was not adequately immunogenic. Children vaccinated <18 months after receiving a BMT had a 4.2-fold increased odds of poor response (P=. 06). Antibody concentrations returned close to baseline levels 9 months after vaccination. Avidity declined significantly as early as 1 month after vaccination and remained low thereafter. Antibody concentration responses to PPV were superior among 9 healthy control children (P=.001); 37 of 38 children with a BMT elicited adequate, persistent immune responses to Haemophilus influenzae conjugate vaccine. Immune responses to PPV in children with a BMT are suboptimal, short lived, and associated with declining avidity. The different kinetics of antibody concentration and avidity indicate that both markers should be used for evaluating pneumococcal vaccines in this high-risk population.

Auxologic data and hormonal profile in long-term survivors of childhood acute lymphoid leukemia.

PURPOSE: Eighty patients, 50 girls and 30 boys 13.5 +/- 4.09 years of age, on continuous first remission, were evaluated 7.9 +/- 3.2 years after the diagnosis of acute lymphoid leukemia (ALL). PATIENTS, METHODS AND RESULTS: All patients were treated according to current protocols. Cranial irradiation dose was 1,800 rad in 10 fractions for 50 patients, and 2,400 rad in 18 fractions for the remaining 30. The mean percentile and SDS for height were 42.5 +/- 26 and -0.3 +/- 1.1 for boys, and 37.8 +/- 15.3 and -0.54 +/- 0.9 for girls, respectively. The final height and the corresponding SDS was 171 +/- 5.75 cm and -0.35 +/- 0.8 for boys, and 158 +/- 7.1 cm and -0.89 +/- 1.1 for girls, respectively. Using skin fold thickness, obesity was observed in a high percentage of patients. The head circumference (HC) percentile was 36.8 +/- 24 for boys and 40.9 +/- 29 for girls, and was even lower (30.96 +/- 25.5) for those who received a radiation dose of 2,400 rad. Menarche was earlier in girls with ALL than in normal girls (11.6 +/- 1.5 vs. 12.4 +/- 1.02 years). Testicular size was within normal limits, except in three boys whose size was at or below the third percentile. In two of them, testes had been irradiated. The mean thyroxin, thyroid-stimulating hormone, and prolactin values were within normal limits (8.6 +/- 2 micrograms/dl, 2.6 +/- 1.1 microU/dl, and 5.9 +/- 4.8 ng/ml, respectively). The somatomedin-C values for patients in the prepubertal stage were 1.49 +/- 0.85 versus 0.96 +/- 0.6 in the controls (p < 0.05), whereas for patients in the pubertal stage they were 1.92 +/- 1 versus 1.88 +/- 1 in the controls. The sex steroid and dehydroepiandrosterone sulfate values were within normal limits. In a high percentage of children, follicle-stimulating hormone and luteinizing hormone values were above the normal range for their age, sex, and pubertal stage. The mean glycosylated hemoglobin values were normal. CONCLUSIONS: 1. Linear growth, although impaired in the group as a whole, is within the normal range for the majority of children with ALL. A small percentage of children have significantly impaired growth, and must be identified early and receive appropriate therapy. 2. Obesity is more frequently present in patients with ALL. 3. HC is lower than expected, indicating impaired brain growth, which is worse in children irradiated with 2,400 rad. 4. Menarche is earlier and the gonadotrophin level is higher than normal, suggestive of either hypothalamic dysfunction, subtle ovarian failure, or both.