Eunkyung Park

Influence of enzyme and transporter polymorphisms on trough imatinib concentration and clinical response in chronic myeloid leukemia patients

BACKGROUND This study explored the impact of genetic polymorphisms in cytochrome P450 (CYP) enzymes and transporters on the plasma trough concentration of imatinib mesylate (IM) and clinical response in chronic myeloid leukemia (CML). PATIENTS AND METHODS In total, 82 patients with CML who had been administered 400 mg IM daily for over 6 months were genotyped for 11 single-nucleotide polymorphisms in nine genes (CYP3A4, CYP3A5, CYP2C9, CYP2C19, CYP2D6, ABCB1, SLC22A1, SLC22A2 and ABCG2) using blood samples. The trough imatinib concentration and clinical responses were assessed 6 months after the initiation of IM therapy. RESULTS The CC, CA and AA genotypes in ABCG2 421C>A gave significantly different frequencies for the major molecular response (MMR) (P = 0.02). However, no significant differences were found between the genotypes of the CYP enzymes and transporters identified in this study and the imatinib plasma trough concentrations and clinical response frequencies, except for the correlation of ABCG2 with MMR. CONCLUSIONS The results of the present study may indicate that the ABCG 421C>A genetic polymorphism influences the MMR of imatinib in patients with CML.

Prognostic factors in primary diffuse large B-cell lymphoma of adrenal gland treated with rituximab-CHOP chemotherapy from the Consortium for Improving Survival of Lymphoma (CISL).

BackgroundThe objective of this study was to identify prognostic factors for survival in patients with primary diffuse large B-cell lymphoma (DLBCL) of the adrenal gland.MethodsThirty one patients diagnosed with primary adrenal DLBCL from 14 Korean institutions and treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) were analyzed.ResultsComplete remission (CR) and overall response rate after R-CHOP chemotherapy were 54.8% and 87.0%. The 2-year estimates of overall survival (OS) and progression-free survival (PFS) were 68.3% and 51.1%. In patients achieving CR, significant prolongations of OS (P = 0.029) and PFS (P = 0.005) were observed. Ann Arbor stage had no influence on OS. There was no significant difference in OS between patients with unilateral involvement of adrenal gland and those with bilateral involvement. When staging was modified to include bilateral adrenal involvement as one extranodal site, early stage (I or II) significantly correlated with longer OS (P = 0.021) and PFS (P < 0.001).ConclusionsContrary to prior reports, our data suggests that outcomes of primary adrenal DLBCL are encouraging using a regimen of R-CHOP, and that achieving CR after R-CHOP is predictive of survival. Likewise, our modified staging system may have prognostic value.

A prospective multicenter observational study of decitabine treatment in Korean patients with myelodysplastic syndrome

Background Decitabine was evaluated for its efficacy and safety in Korean patients with myelodysplastic syndrome with IPSS score of 0.5 or over. Design and Methods Decitabine 20 mg/m2/day was given intravenously over one hour for five consecutive days every four weeks. The primary end point was overall response rate. Results A total of 101 patients were analyzed. The International Prognostic Scoring System risk category was Intermediate-2/High in 47.5%. A median of 5 courses (range 1–18) were delivered. The overall response rate was 55.4% (13 complete responses, one partial response, 23 marrow complete responses, and 19 hematologic improvements). Forty-eight patients (47.5%) showed some hematologic improvement. With a median follow-up duration of 478 days (range 69–595), median overall survival was 17.7 months. Patients who showed hematologic improvement had significantly longer overall survival than those who did not (19.2 vs. 15.9 months, P=0.006 by landmark analysis at six months). The difference in overall survival was evident in the Intermediate-2/High risk group but not in the Intermediate-1 risk group. The progression-free survival and acute myeloid leukemia-free survival were 61.9% and 77.9% at one year, respectively. Among 489 assessable treatment courses, there were 97 fever episodes requiring intravenous antimicrobials. Conclusions Decitabine treatment was feasible and effective in Korean patients with myelodysplastic syndrome, and the overall survival was significantly longer in patients showing hematologic improvement.

Trough plasma imatinib levels are correlated with optimal cytogenetic responses at 6 months after treatment with standard dose of imatinib in newly diagnosed chronic myeloid leukemia

To investigate the correlation of trough imatinib mesylate (IM) levels with cytogenetic or molecular responses, we measured trough IM levels in patients with chronic myeloid leukemia, chronic phase (CML-CP), at 6 months of treatment with a standard dose of IM. Eighty-seven newly diagnosed patients with CML-CP were prospectively enrolled. Seventy-eight patients (89.7%) showed an optimal response (complete or partial cytogenetic response) at 6 months. Trough IM levels were 1378 ± 725 ng/mL. When categorized into two groups, there was a statistically significant difference in numbers of patients with optimal and suboptimal responses at 6 months (group with <1000: 80.6% vs. 19.4%; ≥1000: 94.6% vs. 5.4%; p = 0.032), and in numbers of patients with early major molecular response (early-MMR) and without MMR at 6 months (group with <1000: 3.2% vs. 96.8%; ≥1000: 21.4% vs. 78.6%; p = 0.047). In conclusion, the incidence of optimal cytogenetic response or early-MMR in patients with CML-CP treated with IM for 6 months was significantly higher in those with a trough level of ≥1000 compared with those with a level of <1000. Dose escalation of IM can be one option in patients with CML showing suboptimal response or resistance to the standard dose of IM, especially with low trough plasma IM levels (<1000 ng/mL).

Matched-pair analysis to compare the outcomes of a second salvage auto-SCT to systemic chemotherapy alone in patients with multiple myeloma who relapsed after front-line auto-SCT.

The aims of this study were to investigate the outcomes of second salvage auto-SCT and to identify the impacts of a second auto-SCT compared with systemic chemotherapy alone on disease outcome. Data from 48 patients who underwent second auto-SCT were matched to 144 patients (1:3) who received systemic chemotherapy alone from the Korean Myeloma Registry. Groups were matched for nine potential prognostic factors and compared for treatment outcomes. The median age of matching-pairs at relapse was 55.5 years. A total of 156 patients (81%) received vincristine, doxorubicin and dexamethasone induction therapy before the first auto-SCT. Thirty-five patients (73%) in the second auto-SCT group received novel agent-based therapies before the second auto-SCT, and similar proportion in both groups received novel therapies after relapse of front-line auto-SCT. With a median follow-up of 55.3 months, patients who underwent a second auto-SCT had significantly better median OS (55.5 vs 25.4 months, P=0.035). In multivariate analysis for OS, <18 months time to progression after first auto-SCT, International Staging System III and salvage chemotherapy alone were independent predictors for worse OS. The outcomes of second auto-SCT appear to be superior to those of systemic chemotherapy alone. A randomized trial comparing both treatment strategies is required.

Impact of vitamin D receptor gene polymorphisms on clinical outcomes of HLA‐matched sibling hematopoietic stem cell transplantation

Cho HJ, Shin DY, Kim JH, Bae JY, Lee KH, See CJ, Kim N, Park EK, Ra EK, Lee JE, Hong YC, Kim HK, Park SS, Yoon SS, Lee DS, Han KS, Park MH, Park S, Kim BK, Kim I. Impact of vitamin D receptor gene polymorphisms on clinical outcomes of HLA‐matched sibling hematopoietic stem cell transplantation. 
Clin Transplant 2011 DOI: 10.1111/j.1399‐0012.2011.01523.x. 
© 2011 John Wiley & Sons A/S.

GSTT1 copy number gain is a poor predictive marker for escalated-dose imatinib treatment in chronic myeloid leukemia: genetic predictive marker found using array comparative genomic hybridization

In a study population of 45 patients who were previously enrolled in an imatinib dose escalation trial, genome-wide screening for regions of genetic gains and losses was performed using array comparative genomic hybridization (aCGH). Early molecular response (EMR), defined as >50% reduction in the ratio of BCR-ABL1 to ABL1 within 6 months after dose escalation, was a major endpoint for analysis. After aCGH analysis, copy number change of four genes was investigated in 52 patients as a validation. Copy number gain in 16p11.2 was more frequently observed in patients with EMR than in patients who failed to achieve EMR (P = 0.034). A tendency for increased copy number in 22q11.23 in patients without EMR and for decreased copy number in 17q12 in patients with EMR was observed (P = 0.072 and P = 0.070, respectively). For GSTT1, in 22q11.23, copy number gain was observed in patients without EMR (P = 0.035). GSTT1 copy number gain was related to short time to treatment failure (TTFx) in patients without BCR-ABL1 mutations (P = 0.007). In multivariate analysis, GSTT1 copy number gain was an independent predictive factor for short TTFx (P = 0.020). We conclude that chromosome regions 16p11.2, 22q11.23, and 17q12 are potential locations related to response in imatinib dose escalation therapy for CML. GSTT1 copy number gain is a genetic change affecting outcome in this setting.

Weekly rituximab consolidation following four cycles of R-CHOP induction chemotherapy in very elderly patients with diffuse large B-cell lymphoma: Consortium for improving survival of lymphoma study (CISL).

This study aimed to determine the objective response, toxicity, and clinical outcome of weekly rituximab consolidation after four cycles of R‐CHOP21 in very elderly patients with DLBCL. A prospective, multi‐institutional phase II trial was conducted on patients with previously untreated CD20+ DLBCL who were older than 70 yr. Patients were treated with four cycles of R‐CHOP21 followed by weekly consolidation with rituximab (375mg/m2, four times infusion) (NCT01181999). We also compared the clinical outcomes with an historical case‐matched control group treated conventionally with six cycles of R‐CHOP21. A total of 51 patients with newly diagnosed DLBCL were enrolled at 15 institutes between June 2010 and September 2013. The median age was 76 yr (range: 70–89). Forty‐one of the 51 patients completed the planned rituximab consolidation (R‐consolidation). The overall response rate was 78.4%, comprising 74.5% with a complete response and 3.9% with a partial response. After a median follow‐up of 20.3 months, 2‐yr progression‐free survival and overall survival were 63.9% and 68.7%, respectively. No serious toxicities were reported during rituximab consolidation. Weekly rituximab consolidation following four cycles of R‐CHOP21 resulted in an acceptable response with high tolerability and could be a good compromise between efficacy and safety for elderly patients with DLBCL.

Fludarabine, cytarabine, and attenuated-dose idarubicin (m-FLAI) combination therapy for elderly acute myeloid leukemia patients

We performed a phase II trial to evaluate the efficacy and safety of the modified fludarabine, cytarabine, and attenuated‐dose idarubicin (m‐FLAI) regimen in elderly acute myeloid leukemia (AML) patients. Elderly (≥60 years) AML patients who had not previously received chemotherapy were enrolled in the study. Patients received two consecutive cycles of m‐FLAI chemotherapy as an induction. The m‐FLAI regimen comprised fludarabine (25 mg/m2, days 1–4), cytarabine (1,000 mg/m2, days 1–4), and attenuated‐dose idarubicin (5 mg/m2, days 1–3). The primary end point was complete remission (CR) rate. Secondary end points were overall survival (OS), event‐free survival (EFS), and treatment‐related mortality (TRM). There were 108 patients (median age 68.4 years, M:F = 64:44) enrolled in the study. CR was achieved in 56.5% of patients, and the TRM rate was 21.3%. Median OS and median EFS were 10.2 and 6.6 months, respectively. The mortality at 30 and 60 days was 15 and 21%, respectively. Performance status and comorbidity did not have prognostic value in this patient cohort. Bone marrow expression of CD117 was associated with increased EFS and OS. m‐FLAI is an effective induction regimen for previously untreated AML in elderly patients. In addition, bone‐marrow CD117 expression is an independent favorable prognostic factor in elderly AML patients. (ClinicalTrials.gov number, NCT01247493). Am. J. Hematol. 2013.

Association between kinase insert domain-containing receptor gene polymorphism and haplotypes and ischemic stroke

BACKGROUND Kinase insert domain-containing receptor (KDR), a type 2 vascular endothelial growth factor receptor, plays a crucial role in angiogenesis and vascular integrity of blood vessels. We evaluated whether single nucleotide polymorphisms (SNPs) and haplotype of kinase insert domain-containing receptor (KDR) are associated with increased risk of ischemic stroke in the Korean population. METHODS Totals of 501 patients with ischemic stroke and 478 controls were screened for the KDR -604T>C, +1192G>A, and +1719A>T SNPs. Subgroup analysis was performed to determine whether the effect of KDR polymorphism is specific to certain etiological subtypes of ischemic stroke. In addition, haplotype frequencies of these three SNPs were analyzed in stroke patients and controls. RESULTS The SNP +1719T allele was associated with risk of ischemic stroke in a dose-dependent manner (TT vs. AA: adjusted OR: 1.90, 95% CIs: 1.29-2.81, p=0.001 and false discovery rate (FDR)=0.003). Subgroup analysis showed that the SNP +1719T allele had a slight but significant association with small vessel disease type (TT vs. AA: adjusted OR: 1.91, 95% CIs: 1.11-3.29, p=0.02). There was no association between SNP -604 and SNP +1192 and ischemic stroke risk. In haplotype analysis, the T-G-T (-604/+1192/+1719), T-A-T, and C-G-T haplotypes increased the relative risk of ischemic stroke. CONCLUSIONS The KDR +1719A>T polymorphism and its haplotypes are possible genetic determinants for the risk of ischemic stroke.