Hyoung Jin Kang

Homozygous deletion of CDKN2A (p16, p14) and CDKN2B (p15) genes is a poor prognostic factor in adult but not in childhood B-lineage acute lymphoblastic leukemia: a comparative deletion and hypermethylation study

The biological behavior of childhood B-lineage acute lymphoblastic leukemia (B-ALL) is different from that of adults. We performed a comprehensive analysis of the deletion and the methylation profile of CDKN2A (hereafter identified separately as p16 and p14, for the different proteins encoded) and CDKN2B (hereafter p15) in 91 newly diagnosed B-ALL patients (61 children, 30 adults). The prognostic significance of the profiles of these genes and the association between alterations in these genes and known cytogenetic prognostic factors (BCR/ABL; ETV6/RUNX1, formerly TEL/AML1; MLL rearrangement; and ploidy changes of chromosomes) were also assessed. The prevalence of homozygous deletion, hemizygous deletion, and no deletion of the 9p21 region was 11.5%, 16.4%, and 72.1%, respectively, in children and 30.0%, 20.0%, and 50.0%, respectively, in adults; the higher incidence of homozygous deletion in adults was significant (P=0.029). Homozygous deletion was associated with poor overall survival in adults (P=0.019), but not in children. The incidence of promoter methylation of p16, p14, and p15 was 34.4%, 14.8%, and 34.4%, respectively, in children and 26.7%, 10.0%, and 40.0%, respectively, in adults, with no significant difference between the two groups. No significant association was observed between deletion and methylation or with known cytogenetic prognostic factors. The difference in incidence, distribution, and prognostic effect of homozygous deletion in children and adults may explain the prognostic disparity.

Quantification of Human Plasma-Busulfan Concentration by Liquid Chromatography-Tandem Mass Spectrometry

Background Busulfan, an alkylating agent administered prior to hematopoietic stem cell transplantation, has a narrow therapeutic range and wide variability in metabolism. We developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for rapid and accurate quantification of plasma busulfan. Methods Busulfan was separated and detected using an LC system containing a C18 column equipped with MS/MS. The sample was eluted with a mobile phase gradient for a total run time of 10 min. Plasma busulfan concentration was quantified against a 6-point standard curve in a multiple reaction monitoring mode at mass-to-charge (m/z) 264.1 > 151.1. Precision, recovery, matrix effect, linearity, detection capability, carryover, and stability were evaluated. The range of plasma busulfan concentration was obtained by analyzing samples from 9 children receiving busulfan. Results The coefficients of variation of within-run and within-laboratory precision were all below 5%. Recoveries were all within the range of 100-105%. Linearity was verified from 0 to 5,000 ng/mL. Limit of detection and limit of quantification were 1.56 and 25 ng/mL, respectively. Carryover rate was within allowable limits. Plasma busulfan concentration was stable for 2 weeks at -20℃ and -80℃, but decreased by 25% when the plasma was stored for 24 hr at room temperature, and by <5% in 24 hr at 4℃. The plasma busulfan concentrations were between 347 ng/mL and 5,076 ng/mL. Conclusions Our method using LC-MS/MS enables highly accurate, reproducible, and rapid busulfan monitoring with minimal sample preparation. The method may also enable safe and proper dosage.

The impact of HLA matching on unrelated donor hematopoietic stem cell transplantation in Korean children

Background The impact of HLA matching on outcomes of unrelated donor (URD) hematopoietic stem cell transplantation (HSCT) varies in different racial or ethnic groups. Since little is known about the impact of such matching on URD HSCT in Korean children, we analyzed this issue. Methods We analyzed the outcomes of 142 patients who underwent URD HSCT at 4 Korean medical centers. All patient donor pairs were fully typed for HLA-A, -B, -C, and -DR alleles. Results At a median follow-up of 22 months, 3-year survival rates for patients with 8, 7, and ≤6 matched alleles were 88.4%, 70.7%, and 53.6%, respectively. A single mismatch (Mm) at HLA-B or -C was associated with lower survival compared with that associated with 8 matched alleles. No significant differences were observed between single-allele and single-antigen Mms with respect to survival rate or acute graft-versus-host disease (aGVHD) incidence rates. HLA disparity had a greater impact on the survival of patients with high-risk malignancy than of those with low-risk malignancy. Among pairs with a single Mm, only locus A showed a significant association and higher risk of grade III-IV aGVHD compared to those in patients with 8 matched alleles. Conclusion Disparity in HLA class I, regardless of antigen or allele Mm, adversely affected both survival and grade III-IV aGVHD development. An increased number of HLA Mms was associated with a higher risk of post-transplantation complications. Further investigations using larger cohorts are required to confirm the effects of HLA mismatching on URD HSCT patient outcomes.

The Clinical Significance of Voriconazole Therapeutic Drug Monitoring in Children With Invasive Fungal Infections

Voriconazole is an antifungal drug used to treat fungal infections. This was a retrospective study of 61 children with hemato-oncologic diseases or solid organ transplantation who were administered voriconazole for invasive fungal infections. Of the 61 patients, 31 (50.8%) were in the therapeutic drug monitoring (TDM) group, and 30 (49.2%) were in the non-TDM group. At 12 weeks, treatment failure rate in the non-TDM group was higher than the TDM group (78.6% versus 40.0%, p = 0.038). Drug discontinuation due to adverse events was less frequent in the TDM group than the non-TDM group (26.0% versus 92.3%, p = 0.001). Children required higher dosages to maintain drug levels within the targeted therapeutic range: an average of 8.3 mg/kg/dose in patients <12 years old and 6.9 mg/kg/dose for those ≥12 years old. Treatment failure rates were higher in patients whose voriconazole levels remained below 1.0 mg/L for more than 50% of their treatment duration than those above 1.0 mg/L (71.4% vs. 9.1% after 12 weeks, p = 0.013). Serial monitoring of voriconazole levels in children is important for improving treatment response and preventing unnecessary drug discontinuation. Higher dosages are needed in children to reach therapeutic range.

1337PDEFFECTS OF PATIENT CHARACTERISTICS ON THE EFFICACY AND SAFETY OF APREPITANT IN A PEDIATRIC POPULATION

– In the primary analysis from this study, treatment with aprepitant resulted in a greater proportion of patients achieving complete response (CR) in the delayed phase (25–120 hours after chemotherapy initiation) than the standard regimen alone (51% vs 26%, P < 0.0001) 7 • CR was defined as “no vomiting or retching and no use of rescue medication” – CR was also greater with the aprepitant regimen vs the control regimen in the acute (66% vs 52%; P = 0.0135) and overall phases (40% vs 20%; P = 0.0002) 7

1338PDEMESIS RATE AND RESCUE MEDICATION USE IN CHILDREN USING APREPITANT TO PREVENT CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING (CINV)

ABSTRACT Aim: Aprepitant, in combination with a 5HT3-antagonist and a corticosteroid, is indicated for prevention of CINV due to highly/moderately emetogenic chemotherapy (chemo) in adults. To evaluate aprepitant for CINV prevention in children, a phase III, randomized, double-blind, active-comparator study was conducted in pediatric patients (NCT01362530). Methods: Patients ages 12-17 years (y) undergoing highly/moderately emetogenic chemo received aprepitant capsule 125u2003mg + ondansetron before chemo (Day 1) + aprepitant capsule 80u2003mg (Days 2-3), OR placebo (Days 1-3) + ondansetron (Day 1). Patients 6 months to Results: Efficacy and safety were evaluated in 152 aprepitant and 150 control patients. The proportion of patients experiencing no emetic episodes was higher in the aprepitant regimen vs the control regimen during both acute (71.1% vs 53.3%) and delayed (55.3% vs 28.0%) phases. The median time to first vomiting (overall) was significantly longer for aprepitant vs control (94.5 vs 26.0 hours; P Conclusions: In pediatric patients with cancer receiving emetogenic chemo, the 3-day aprepitant regimen prevented emetic episodes and reduced the need for rescue medication compared with a 5HT3-antagonist regimen without aprepitant. Disclosure: H.J. Kang: Received research funding from Merck & Co., Inc. MK869 PN208 study involvement; S. Loftus: Full-time employee of Merck & Co., Inc., with stock ownership; A. Taylor: Full-time employee of Merck & Co., Inc.; C. Dicristina: Full-time employee of Merck & Co., Inc.; S. Green: Full-time employee of Merck & Co., Inc., with stock ownership. All other authors have declared no conflicts of interest.