Kyoo Hyung Lee

Randomized Trial of Myeloablative Conditioning Regimens: Busulfan Plus Cyclophosphamide Versus Busulfan Plus Fludarabine

PURPOSE We conducted a phase III randomized clinical trial to compare two myeloablative conditioning regimens for allogeneic hematopoietic cell transplantation (HCT) in patients with leukemia and myelodysplastic syndrome. PATIENTS AND METHODS After randomization, 64 patients received busulfan (3.2 mg/kg per day × 4 days) plus cyclophosphamide (60 mg/kg per day × 2 days; BuCy), and 62 patients received busulfan (same dose and schedule) plus fludarabine (30 mg/m(2) per day × 5 days; BuFlu). RESULTS The median age was 41 years (range, 17 to 59 years). Five patients in the BuFlu arm experienced graft failure (primary, n = 1; secondary, n = 4). At 4 weeks after HCT, the median percentage of recipient hematopoietic chimerism was significantly greater in the BuFlu arm (0% v 5.5%; P < .001), and complete donor chimerism was greater in the BuCy arm (97.2% v 44.4%; P < .001). Severe (grade 3 or higher) infection and gastrointestinal adverse events were significantly more common in the BuCy arm, but the frequencies of hepatic adverse events were similar in the two arms. Nonrelapse mortality was similar in the two arms, but the BuCy arm had better overall survival (OS), relapse-free survival (RFS), and event-free survival (EFS; OS at 2 years, 67.4% v 41.4%, P = .014; RFS, 74.7% v 54.9%, P = .027; EFS, 60.7% v 36.0%, P = .014). CONCLUSION Our results indicate that the BuFlu regimen is not a suitable replacement for the BuCy regimen in young adults who are eligible for myeloablative conditioning therapy for allogeneic HCT.

HIGH PREVALENCE OF HEPATITIS B AND HEPATITIS C VIRUS INFECTIONS IN KOREAN PATIENTS WITH HEMATOPOIETIC MALIGNANCIES

We performed a large case–control study (3,932 cases, 15,562 controls) to investigate the association of hepatitis B virus (HBV) and hepatitis C virus (HCV) with hematopoietic malignancies in Korea, where HBV is endemic. HBV was present in 636 control patients (4.1%), 333 lymphoma patients (12.4%), and 75 leukemia patients (6.0%). HCV infection was present in 173 control patients (1.1%), 76 lymphoma patients (2.8%), and 18 leukemia patients (1.4%). Co-infection of HBV and HCV was present in one (0.007%) control patient, seven lymphoma patients (0.3%), and one leukemia patient (0.08%). HBV infection was associated with increased risks for most subtypes of B and T/NK-cell lymphomas, Hodgkin’s lymphoma, and acute myeloid leukemia. HCV infection was associated with increased risks for diffuse large B cell lymphoma, extranodal marginal zone B cell lymphoma, peripheral T cell lymphoma, and acute lymphoid leukemia B cell early pre-B type. HBV seems to have a more important role than HCV in the pathogenesis of specific hematologic malignancies in Korea.

Telomerase activity and its clinicopathological significance in gastric cancer

In order to assess the role of telomerase in development of malignant gastric cancer, we measured the telomerase activity in gastric cancer tissues and normal tissues obtained from 95 patients by employing recently developed sensitive PCR (polymerase chain reaction)-based telomerase assay (telomeric repeat amplification protocol, TRAP). We also investigated how telomerase activity related to other clinicopathological findings including DNA ploidy and K-RAS gene point mutation. The telomerase activity was present in 85 of the 95 gastric cancer tissues, whereas we detected no telomerase activity in any normal tissue. The incidence of telomerase activity in gastric cancer tissues was not correlated to age, sex, tumour stage, histological grade, DNA ploidy or K-RAS mutation. Disease-free or overall survival of patients having tumours with detectable telomerase activity was not significantly different from that of those without telomerase activity. These findings suggest that telomerase may play a key role in the establishment and progression of the gastric cancer and further studies will be needed to elucidate the biological role of telomerase in gastric cancer.

Prognostic implications of the immunophenotype in biphenotypic acute leukemia

The present study retrospectively analyzed clinicopathological and clinical data from 43 adult patients with biphenotypic acute leukemia (BAL) from 11 Korean institutes. The incidence of BAL was 2.1% among acute leukemias. In terms of immunophenotype, 31 patients had myeloid plus B-lymphoid (M + B), 10 had myeloid plus T-lymphoid (M + T), one had myeloid plus B-lymphoid plus T-lymphoid (M + B + T), and one had B-lymphoid plus T-lymphoid (B + T). Patients with M + T phenotype had significantly lower CR rate (55.6% vs. 88.0%, P = 0.039) and lower overall survival (0% vs. 33.9% at 5 years, P = 0.028) than those with M + B phenotype. Our results suggest that immunophenotype has prognostic implications in adult patients with BAL.

Influence of GST gene polymorphisms on the clearance of intravenous busulfan in adult patients undergoing hematopoietic cell transplantation.

Intravenous (i.v.) busulfan can produce a more consistent pharmacokinetic profile than oral formulations can, but nonetheless, significant interpatient variability is evident. We investigated the influence of polymorphisms of 3 GST isozyme genes (GSTA1, GSTM1, and GSTT1) on i.v. busulfan clearance. Fifty-eight adult patients who received 3.2 mg/kg/day of busulfan as conditioning for hematopoietic cell transplantation were included in this study. Stepwise multiple linear regression demonstrated that GSTA1 variant GSTA1∗B (P = .004), GSTM1/GSTT1 double-null genotype (P = .039), and actual body weight (P = .001) were significantly associated with lower clearance of i.v. busulfan. A trend test analyzing the overall effect of GST genotype on busulfan pharmacokinetics, combining GSTA1 gene polymorphism and the number of GSTM1- and GSTT-null genotypes, showed a significant correlation between GST genotype and busulfan clearance (P = .001). The clearance of i.v. busulfan was similar between patients with GSTA1∗A/∗A and GSTM1/GSTT1 double-null genotypes and those with GSTA1∗A/∗B and GSTM1/GSTT1 double-positive genotypes. In conclusion, a pharmacogenetic approach using GST gene polymorphisms may be valuable in optimizing the i.v. busulfan dosage scheme. Our results also highlight the importance of including polygenic analyses and addressing interactions among isozyme genes in pharmacogenetic studies.

Decreased incidence of febrile episodes with antibiotic prophylaxis in the treatment of decitabine for myelodysplastic syndrome

We analyzed the role of antibiotic prophylaxis during decitabine treatment for MDS. The primary endpoint was the incidence of febrile episodes. The total number of decitabine cycles given to 28 patients was 131, and febrile episodes occurred in 15 cycles (11.5%). Antibiotic prophylaxis was orally administered in 95 cycles (72.5%). Febrile episodes were significantly less frequent among patients who received antibiotic prophylaxis (7.4%) than in those without prophylaxis (22.2%) (P=0.017). In conclusion, antibiotic prophylaxis reduced the incidence of febrile episodes in patients who received decitabine treatment for MDS, especially at earlier cycles and in the presence of severe cytopenia.

Deferasirox improves hematologic and hepatic function with effective reduction of serum ferritin and liver iron concentration in transfusional iron overload patients with myelodysplastic syndrome or aplastic anemia

Transfusional iron overload and its consequences are challenges in chronically transfused patients with myelodysplastic syndromes (MDSs) or aplastic anemia (AA).

Phase II trial of recombinant human interleukin-2 and interferon-alpha-2a: Implications for the treatment of patients with metastatic melanoma

An intensive in‐patient Phase II study of continuous infusion recombinant human interleukin‐2 (rhIL‐2) 3 × 106 Roche units (9 MIU/m2)/day plus intramuscular injection of interferon‐alpha‐2a (rIFN‐α‐2a) 5 × 106 U/m2/day, four consecutive days per week, was performed to determine whether four consecutive weeks of such treatment every 6 to 8 weeks might yield a response rate of 30 to 40%, supporting an additive or synergistic effect of these agents in patients with metastatic melanoma.

Single nucleotide polymorphism of Wilms’ tumor 1 gene rs16754 in Korean patients with cytogenetically normal acute myeloid leukemia

A recent study from Germany showed that WT1 single nucleotide polymorphism (SNP) rs16754 was an independent prognostic factor in cytogenetically normal acute myeloid leukemia (CN-AML). We analyzed clinical impact of the WT1 rs16754 genotype on disease characteristics and outcomes in Korean patients with CN-AML. A total of 73 patients with CN-AML were included in the study. All patients received standard induction chemotherapy and their bone marrow or peripheral blood samples were cryopreserved at the time of diagnosis. WT1 exons 7 and 9 were amplified using polymerase chain reaction and directly sequenced. The genotype frequency for WT1 rs16754 was 6.8% for AA, 39.7% for GA, and 53.4% for GG. G was a minor allele in German population, whereas it was a major allele in Korean (13.7% vs. 73.3%, P < 0.001). Complete remission was induced in 85.3% of patients with GA/AA and 84.6% of those with GG (P = 0.936). Survival rates were also similar between patients with GG and those with GA/AA. Asian and Western populations exhibited significant differences in allele and genotype frequencies of WT1 rs16754. In Korean patients with CN-AML, WT1 SNP rs16754 had no significant impact on clinical outcomes and further investigations are needed to define prognostic implication of WT1 SNP rs16754 in CN-AML.

A randomized double-blind trial of ondansetron alone versus in combination with dexamethasone versus in combination with dexamethasone and lorazepam in the prevention of emesis due to cisplatin-based chemotherapy.

ObjectiveTo compare the effectiveness and side effects of antiemetic regimens using ondansetron alone (O) versus ondansetron plus dexamethasone (OD) versus ondansetron plus dexamethasone plus lorazepam (ODA) in the prevention of emesis induced by cisplatin-based chemotherapy. DesignRandomized, double-blind trial. Patients and MethodsIn this study, 75 patients who were receiving cisplatin (60 mg/m2) on day 1 and 5-fluorouracil (1,000 mg/m2) on day 2 to day 6 were enrolled. Patients were randomized to one of three treatment regimens: O, OD, or ODA. The patients assigned to O regimen received ondansetron 8 mg intravenously as a loading dose 15 minutes prior to cisplatin, then 1 mg/h continuous IV infusion (24 mg/day) for 48 hours. OD regimen consisted of ondansetron given as above plus dexamethasone administered at a dose of 10 mg IV injection every 12 hours for 3 days. ODA regimen was OD regimen plus lorazepam administered at a dose of 0.5 mg orally every 6 hours for 3 days. To ensure blinding, O group patients received 10 ml placebo-saline IV injection every 12 hours for 3 days, and O and OD group patients received placebo tablets orally every 6 hours for 3 days. ResultsOne patient did not receive assigned antiemetic regimen and was excluded from the analysis. In the acute phase, complete control of emesis was seen in 85% of all patients, and there was no significant difference among the three groups (p = .442). Complete control of nausea during the acute phase was achieved in 10 patients (41.2%) treated with O regimen alone, in 23 patients (92.0%) treated with OD regimen, and in 16 patients (64.0%) treated with ODA regimen (p < .001). In the delayed phase, 68% of patients who received the three-drug combination (ODA) and 56% of patients who received the two-drug combination (OD) obtained complete control of emesis, as opposed to 29% who were given ondansetron alone (p < .021). The incidences of headache, flushing, dry mouth, hiccups, and constipation were mild and tolerable and did not differ among the three groups. DiscussionOndansetron was very effective in the prevention of nausea and vomiting during the acute phase after cisplatin administration. In treating delayed nausea and vomiting, although the results of three regimens were still disappointing, the combination of ondansetron plus dexamethasone or plus lorazepam provided superior results. Patients who received the lorazepam-containing regimen appeared more comfortable and less restless than those who were given other regimens.