Sung Nam Lim

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.

Allogeneic hematopoietic cell transplantation for myelodysplastic syndrome: prognostic significance of pre-transplant IPSS score and comorbidity

We analyzed the clinical significance of pre-transplant International Prognostic Scoring System (IPSS) score and comorbidity in 68 patients who underwent allogeneic hematopoietic cell transplantation (HCT) for myelodysplastic syndrome (MDS) (n=48) or acute myeloid leukemia evolved from MDS (n=20) between December 1995 and January 2008 in a single institute. During a median follow-up period of 41.0 months (range, 3.2–132.0 months), 27 patients died, and 7 relapsed. The 5-year probabilities of overall survival (OS) and event-free survival (EFS) were 60.0 and 57.4%, respectively, and the 5-year cumulative incidences of non-relapse mortality (CINRM) and relapse were 32.7 and 9.9%, respectively. OS, EFS, and CINRM were significantly different according to pre-transplant IPSS score and presence of pre-transplant comorbidity, which were independent risk factors along with Karnofsky performance score in multivariate analyses. In conclusion, pre-transplant IPSS score and comorbidity may stratify the risk of post transplant outcomes in MDS.

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.

A Case of Primary Adrenal Diffuse Large B-cell Lymphoma Achieving Complete Remission with Rituximab-CHOP Chemotherapy

Primary adrenal lymphoma is a very rare extranodal lymphoma; its clinical features consist of a high incidence of bilateral adrenal involvement and diffuse large B-cell lymphoma. We report a patient with primary bilateral adrenal diffuse large B-cell lyphoma who achieved complete remission with R-CHOP (rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. A 52-yr-old man presented with fever and progressive fatigue for 3 months. Computed tomography (CT) scans of the abdomen and pelvis demonstrated large bilateral adrenal masses, and a needle biopsy of the left adrenal mass revealed diffuse large B-cell lymphoma. After 6 cycles of R-CHOP chemotherapy, CT scans showed no residual disease. To our knowledge, this is the second report to date of a patient with primary bilateral adrenal diffuse large B-cell lymphoma who achieved complete remission using R-CHOP chemotherapy.

Reevaluation of the National Institutes of Health criteria for classification and scoring of chronic GVHD

We used the National Institutes of Health (NIH) criteria for the diagnosis, classification and scoring of chronic GVHD (cGVHD) to reevaluate patients with cGVHD originally diagnosed using classic criteria. We retrieved data from 236 patients diagnosed with cGVHD on the basis of classic criteria. Excluding 20 ‘liver-alone’ patients, we re-categorized 216 patients in keeping with the NIH criteria. Twenty patients were reclassified as having acute GVHD and 196 patients as having cGVHD (170 ‘classic chronic’ (Cl-Ch) and 26 ‘overlap chronic’ (Ov-Ch)). The 5-year GVHD-specific survival (GSS) was significantly different between the two cGVHD subtypes, specifically 87.3% for Cl-Ch vs 70.2% for Ov-Ch (P=0.006). The NIH severity criteria were effective in expecting 5-year GSS rates at both the onset (93.5, 81.3 and 79.7% (P=0.047)) and peak intensity of the disease (100, 89.7 and 78.7% (P=0.004) for the mild, moderate and severe grade, respectively). Multivariate analysis showed that NIH severity criteria were independently significant prognostic factors for GSS (mild vs moderate, HR 4.35, P=0.036; mild vs severe, HR 5.25, P=0.020). Our results support the role of the NIH criteria in classifying cGVHD and in assessing the severity of the disease to predict patient prognosis of cGVHD.

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.

Allogeneic hematopoietic cell transplantation in adult patients with myelodysplastic/myeloproliferative neoplasms

Background In adults, the 2 main types of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are chronic myelomonocytic leukemia (CMML) and atypical chronic myeloid leukemia (aCML). Both are associated with a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) is the only known curative treatment modality for these diseases, but data on outcomes following such treatment are limited. We analyzed the outcomes of patients with MDS/MPN after allogeneic HCT. Methods This retrospective study included 10 patients with MDS/MPN who received allogeneic HCT at Asan Medical Center from 2002 to 2010. Of these 10 patients, 7 had CMML, 2 had aCML, and 1 had unclassifiable MDS/MPN. Five patients received a myeloablative conditioning (MAC) regimen (busulfan-cyclophosphamide), and 5 received reduced-intensity conditioning (RIC) regimen. Results Neutrophil engraftment was achieved in all patients. After a median follow-up of 47.5 months among surviving patients, 4 had relapsed and 5 had died. There was only 1 treatment-related death. The 5-year rates of overall, relapse-free, and event-free survival were 42.2%, 51.9%, and 46.7%, respectively. Relapse was the leading cause of treatment failure, and all relapses were observed in patients who had received RIC and who did not develop chronic graft-versus-host disease. Conclusion Allogeneic HCT can induce durable remission in patients with MDS/MPN, but RIC cannot replace MAC in patients eligible for myeloablative treatments.