Yunsuk Choi

Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for never-smokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastasis

Considering whole-brain radiotherapy (WBRT) for asymptomatic brain metastases can reduce performance status and delay systemic treatment, primary chemotherapy can be a feasible alternative treatment. Good and rapid response to epidermal growth factor tyrosine kinase inhibitor (EGFR TKI) treatment makes this an attractive option for never-smokers with adenocarcinoma of the lung. Between January 2005 and August 2007, 23 Korean never-smoking patients with adenocarcinoma of the lung who had synchronous asymptomatic brain metastasis were consecutively treated with EGFR TKI therapy, either gefitinib 250 mg or erlotinib 150 mg once daily, as first-line treatment after giving informed consent, until disease progression, unacceptable toxicity or patients refusal. They have not received either any prior chemotherapy or any radiotherapy including stereotactic radiosurgery. Objective tumor responses were assessed 1 month after treatment and then every 2 months or when clinically indicated. Out of the 23 patients treated, 16 achieved a PR and 3 experienced stable disease (SD) while 4 experienced progressive disease (PD), resulting in a response rate of 69.6% and a disease control rate of 82.6%. Intracranial tumor responses were observed in 17 patients (73.9%). After a median follow-up of 21.8 months, the median progression-free and overall survival (OS) time was 7.1 and 18.8 months, respectively. Eleven patients received WBRT with a median time-to-local-treatment for intracranial tumors of 19.3 months. In conclusion, EGFR TKI treatment showed promising antitumor activity against both intracranial and extracranial tumors in chemotherapy-naïve never-smokers with adenocarcinoma of the lung. Therefore, these agents should be considered as the treatment of choice in this clinical setting.

Feasibility of hypomethylating agents followed by allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome

The role of hypomethylating agent therapy (HMT) as a bridge to allogeneic hematopoietic cell transplantation (alloHCT) in patients with myelodysplastic syndrome (MDS) remains undetermined. We investigated the feasibility of HMT followed by alloHCT in patients with MDS. In all, 19 patients who received HMT followed by alloHCT were analyzed. A total of 7 patients were classified as low-risk and 12 as high-risk, based on World Health Organization (WHO) classification at the time of HMT. HMT consisted of decitabine in 9 patients and azacitidine in 10. After HMT, two patients achieved CR, six mCR, three hematologic improvement alone, and six SD in terms of best response. HMT did not alter WHO classification in 15 patients (79%), whereas 1 patient (5%) improved and 3 (16%) progressed to AML. Most patients (95%) received a non-myeloablative conditioning regimen based on fludarabine/BU/anti-thymocyte globulin, and peripheral blood-mobilized stem cells. Neutrophil and platelet engraftments were achieved in 95 and 79% of patients, respectively. The incidences of acute and chronic GVHD were 42 and 26%, respectively. In all, 2-year OS rates were 68%, and the overall outcomes of those who achieved CR/mCR with HMT tended to be superior to those without CR/mCR. HMT followed by alloHCT was a feasible and effective treatment strategy for patients with MDS.

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.

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.

Clinical Characteristics and Prognostic Factors of Adenoid Cystic Carcinoma of the Head and Neck

This study was intended to evaluate prognostic factors and the role of postoperative radiotherapy (RT) in patients with adenoid cystic carcinoma (ACC) of the head and neck (ACCHN).

Tandem high-dose chemotherapy and autologous stem cell transplantation in patients with high-risk neuroblastoma: results of SMC NB-2004 study.

From January 2004 to December 2008, 50 consecutive patients with high-risk neuroblastoma were assigned to receive tandem HDCT (high-dose chemotherapy)/auto-SCT after nine cycles of induction chemotherapy. CEC (carboplatin+etoposide+cyclophosphamide) regimen and TM (thiotepa+melphalan)-TBI regimen (or TM regimen for stage 3 patients) were the first and second HDCT regimens. Local radiotherapy, differentiation therapy with 13-cis-retinoid acid and immunotherapy with interleukin-2 were given after tandem HDCT/auto-SCT. Of the 50 patients, 49 underwent a first HDCT/auto-SCT and 47 underwent a second HDCT/auto-SCT. The tumor relapsed or progressed in 14 patients, secondary malignancy developed in one patient and one patient died from chronic lung disease. Therefore, 34 patients remained event free with a median follow-up of 54.5 months (range, 14–94 months) from diagnosis. The probabilities of 5-year OS and EFS for all 50 patients were 77.0% (95% confidence interval (CI), 63.7–90.3) and 71.4% (95% CI, 58.7–84.1), respectively. However, all patients who remained event free for >3 years after tandem HDCT/auto-SCT experienced late adverse effects. Chemotherapeutic dose-escalation strategy using tandem HDCT/auto-SCT was very encouraging for survival. However, further studies incorporating newer treatment modalities are needed to reduce late adverse effects without jeopardizing the survival rate.

Feasible Outcomes of T Cell–Replete Haploidentical Stem Cell Transplantation with Reduced-Intensity Conditioning in Patients with Myelodysplastic Syndrome

Even with the recent optimization of haploidentical stem cell transplantation (SCT), its role for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia evolving from MDS (sAML) should be validated. We analyzed the outcomes of consecutive 60 patients with MDS or sAML who received T cell-replete haploidentical SCT after reduced-intensity conditioning with fludarabine, busulfan, and rabbit antithymocyte globuline ± 800 cGy total body irradiation. Patients achieved a rapid neutrophil engraftment after a median of 12 days (range, 8 to 23) and an early immune reconstitution without high incidences of acute graft-versus-host disease (GVHD) II to IV and chronic GVHD (36.7% and 48.3%, respectively). After a median follow-up of 4 years, incidence of relapse and nonrelapse mortality and rate of overall survival and disease-free survival was 34.8%, 23.3%, 46.8%, and 41.9%, respectively. In multivariate analysis, the disease status at peak was a significant predictor for relapse (lower-risk MDS versus higher-risk MDS or sAML; hazard ratio [HR], 5.69; 95% confidence interval [CI], 1.45 to 22.29; P = .013) and disease-free survival (HR, 4.44; 95% CI, 1.14 to 17.34; P = .032). Chronic GVHD was an additional significant predictor for relapse (no versus yes; HR, 2.87; 95% CI, 1.03 to 7.51; P = .043). Our T cell-replete haploidentical SCT may be a feasible option for patients with MDS and sAML without conventional donors.

Somatic mutations predict outcomes of hypomethylating therapy in patients with myelodysplastic syndrome.

Although hypomethylating therapy (HMT) is the first line therapy in higher-risk myelodysplastic syndromes (MDS), predicting response to HMT remains an unresolved issue. We aimed to identify mutations associated with response to HMT and survival in MDS. A total of 107 Korean patients with MDS who underwent HMT (57 responders and 50 non-responders) were enrolled. Targeted deep sequencing (median depth of coverage 1,623X) was performed for 26 candidate MDS genes. In multivariate analysis, no mutation was significantly associated with response to HMT, but a lower hemoglobin level (<10g/dL, OR 3.56, 95% CI 1.22-10.33) and low platelet count (<50,000/μL, OR 2.49, 95% CI 1.05-5.93) were independent markers of poor response to HMT. In the subgroup analysis by type of HMT agents, U2AF1 mutation was significantly associated with non-response to azacitidine, which was consistent in multivariate analysis (OR 14.96, 95% CI 1.67-134.18). Regarding overall survival, mutations in DNMT1 (P=0.031), DNMT3A (P=0.006), RAS (P=0.043), and TP53 (P=0.008), and two clinical variables (male-gender, P=0.002; IPSS-R H/VH, P=0.026) were independent predicting factors of poor prognosis. For AML-free survival, mutations in DNMT3A (P<0.001), RAS (P=0.001), and TP53 (P=0.047), and two clinical variables (male-gender, P=0.024; IPSS-R H/VH, P=0.005) were independent predicting factors of poor prognosis. By combining these mutations and clinical predictors, we developed a quantitative scoring model for response to azacitidine, overall- and AML-free survival. Response to azacitidine and survival rates became worse significantly with increasing risk-scores. This scoring model can make prognosis prediction more reliable and clinically applicable.