Jee Hyun Kong

Early Imatinib Mesylate-Induced Hepatotoxicity in Chronic Myelogenous Leukaemia

Imatinib mesylate is the first molecule of targeted therapy in chronic myelogenous leukaemia inhibiting constitutively activated BCR-ABL kinase. There are no long-term follow-up studies of large sample sizes to assess the toxicity of the use of imatinib mesylate over 10 years. Several cases of hepatotoxicity, including fatal liver failure, have been associated with the long-term use of imatinib mesylate. We report here on a patient who experienced immediate dominant cholestatic damage of the liver and mild hepatocyte damage during imatinib mesylate therapy. This differs from most reports showing dominantly acute hepatitis with necrosis associated with the use of imatinib mesylate.

The IFNG (IFN-γ) Genotype Predicts Cytogenetic and Molecular Response to Imatinib Therapy in Chronic Myeloid Leukemia

Purpose: The present study analyzed treatment outcomes of imatinib therapy by interindividual genetic variants in candidate biological pathways of chronic myeloid leukemia (CML) such as apoptosis, angiogenesis, IFN-γ signaling pathways, or drug transport/metabolism of imatinib. Experimental Design: Peripheral blood DNAs were genotyped for 79 single nucleotide polymorphism markers involved in the pathways of apoptosis, angiogenesis, myeloid cell growth, xenobiotic metabolism, WT1 signaling, IFN signaling, and others in CML patients who were included in discovery (n = 229, Canada) and validation cohorts (n = 187, Korea). Results: We found several genotypes associated with complete cytogenetic response: IFNG (rs1861494, rs2069705), FASL (rs763110), FAS (rs2234767, rs2234978), VEGFR2 (rs1531289), and WT1 (rs2234590); with major molecular response: IFNG (rs1861494, rs2069705), BIRC5 (rs9904341), FAS (rs2234978), and ABCG2 (rs2231142); with loss of response: IFNG (rs2069705), IFNGR2 (rs9808753), BIRC5 (rs9904341), and ORM (rs3182041); and with treatment failure: IFNG (rs2069705), JAK3 (rs3212713), and ORM (rs3182041). External validation for the above significant genotypes confirmed that the IFNG genotype (rs2069705) was predictive of complete cytogenetic response (hazard ratio, 2.17; P < 0.001) and major molecular response (hazard ratio, 1.96; P = 0.0001) in validation cohorts of Korean ethnicity. Conclusions: The IFNG genotype was predictive for response to imatinib therapy, suggesting potential involvement of the IFN-γ signaling pathway in the mechanism of action of imatinib in CML. Clin Cancer Res; 16(21); 5339–50. ©2010 AACR.

Predictive Value of the ERCC1 Expression for Treatment Response and Survival in Advanced Gastric Cancer Patients Receiving Cisplatin-based First-line Chemotherapy.

PURPOSE The aim of this study was to determine whether the ERCC1 expression is effective to predict the clinical outcomes of patients with advanced gastric cancer (AGC) and who were treated with cisplatin-based first-line chemotherapy. MATERIALS AND METHODS A total of 89 measurable AGC patients received cisplatin and capecitabine, with or without epirubicin, as a part of a randomized phase II study. Patients were included for the current molecular analysis if they had received two or more cycles of chemotherapy, their objective tumor responses were measured and if their paraffin-embedded tumor samples were available. The ERCC1 expression was examined by performing immunohistochemical (IHC) staining, and the patients were divided into two groups (positive or negative) according to the presence of IHC staining of the tumor cell nuclei. RESULTS Of the 32 eligible patients, 21 patients (66%) had tumor with a positive expression of ERCC1 and the remaining 11 patients had tumor with a negative ERCC1-expression. The ERCC1-negative patients achieved a higher response rate than that of the ERCC1-positive patients (44% vs. 28%, respectively), although the difference was not statistically significant (p=0.42). The median survival time for the all patients was 14.6 months (95% CI: 13.6 to 15.6 months). The one-year survival rate was similar for the ERCC1-negative patients (61%) and the ERCC1-positive patients (70%). CONCLUSION In the current study, the tumor ERCC1 expression by IHC staining could not predict the clinical response or survival of AGC patients who were treated with cisplatin-based first-line chemotherapy. The ERCC1 protein expression does not appear to be a useful tool for the selection of tailored chemotherapy for these patients.

Phase III Clinical Trial (RERISE study) Results of Efficacy and Safety of Radotinib Compared with Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia

Purpose: Radotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) approved in Korea for chronic phase chronic myeloid leukemia (CML-CP) in patients newly diagnosed or with insufficient response to other TKIs. This study was conducted to evaluate the efficacy and safety of radotinib as first-line therapy for CML-CP. Experimental Design: This multinational, open-label study assigned patients (1:1:1) to one of two twice-daily radotinib doses, or imatinib daily. The primary endpoint was major molecular response (MMR) by 12 months. Results: Two hundred forty-one patients were randomized to receive radotinib 300 mg (n = 79) or 400 mg twice-daily (n = 81), or imatinib 400 mg daily (n = 81). MMR rates by 12 months were higher in patients receiving radotinib 300 mg (52%) or radotinib 400 mg twice-daily (46%) versus imatinib (30%; P = 0.0044 and P = 0.0342, respectively). Complete cytogenetic response (CCyR) rates by 12 months were higher for radotinib 300 mg (91%) versus imatinib (77%; P = 0.0120). Early molecular response at 3 months occurred in 86% and 87% of patients receiving radotinib 300 mg and radotinib 400 mg, respectively, and 71% of those receiving imatinib. By 12 months, no patients had progression to accelerated phase or blast crisis. Most adverse events were manageable with dose reduction. Conclusions: Radotinib demonstrated superiority over imatinib in CCyR and MMR in patients newly diagnosed with Philadelphia chromosome–positive CML-CP. This trial was registered at www.clinicaltrials.gov as NCT01511289. Clin Cancer Res; 23(23); 7180–8. ©2017 AACR.

Improved prognostic stratification using NCCN- and GELTAMOinternational prognostic index in patients with diffuse large B-cell lymphoma

The National Comprehensive Cancer Network (NCCN)-International Prognostic Index (IPI) and GELTAMO (Grupo Español de Linfomas/Trasplante Autólogo de Médula Ósea)-IPI were developed to enable better risk prediction of patients with diffuse large B-cell lymphoma (DLBCL). The present study compared the effectiveness of risk prediction between IPI, NCCN-IPI, and GELTAMO-IPI in patients with DLBCL particularly in terms of determining high-risk patients. Among 439 patients who were enrolled to a prospective DLBCL cohort treated with R-CHOP immunochemotherapy, risk groups were classified according to the three IPIs and the prognostic significance of individual IPI factors and IPI models were analyzed and compared. All three IPI effectively separated the analyzed patients into four risk groups according to overall survival (OS). Estimated 5-year OS of patients classified as high-risk according to the IPI was 45.7%, suggesting that the IPI is limited in the selection of patients who are expected to have a poor outcome. In contrast, the 5-year OS of patients stratified as high-risk according to NCCN- and GELTAMO-IPI was 31.4% and 21.9%, respectively. The results indicate that NCCN- and GELTAMO-IPI are better than the IPI in predicting patients with poor prognosis, suggesting the superiority of enhanced, next-generation IPIs for DLBCL.

Outcomes of Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia Following an Elective Switch From Second-Generation Tyrosine Kinase Inhibitor to Imatinib

Abstract The second‐generation tyrosine kinase inhibitors (TKIs) (2G‐TKIs) dasatinib (DAS) and nilotinib (NIL) yield faster responses in newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML) as compared with imatinib (IM); however, long‐term safety of these agents is a growing concern. We identified 20 patients with CP‐CML diagnosed between August 2013 and October 2016 who initiated 2G‐TKIs and were then switched after optimal response at 3 months to IM. Second‐generation TKIs initiated were DAS (n = 15), NIL (n = 3), or both sequentially due to intolerance (n = 1). One other patient initiated therapy with ponatinib on trial. Response was assessed by quantitative reverse‐transcriptase polymerase chain reaction (qRT‐PCR) for BCR‐ABL1 levels every 3 months and in patients with qRT‐PCR values less than 10% at 3 months, IM was started at 400 mg/d. IM was well tolerated except in 2 patients who required dose‐reduction and discontinuation due to grade 2 skin rash (1) and grade 2 anxiety (1). After initiation of IM therapy, the BCR‐ABL1 qRT‐PCR levels trended down as expected. At 12 months 16 (84.2%) of 19 evaluable patients showed a 3 log (major molecular remission) or better reduction in their PCR levels. In conclusion, this retrospective analysis shows that IM can be safely and effectively administered following optimal response to 2G‐TKIs. A prospective trial exploring this approach is currently enrolling and will be needed to confirm the safety and efficacy of this therapeutic approach.

Highly elevated serum lactate dehydrogenase is associated with central nervous system relapse in patients with diffuse large B-cell lymphoma: Results of a multicenter prospective cohort study

Central nervous system involvement remains a challenging issue in the treatment of patients with diffuse large B-cell lymphoma. We conducted a prospective cohort study with newly diagnosed diffuse large B-cell lymphoma patients receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone to identify incidence and risk factors for central nervous system involvement. Among 595 patients, 279 patients received pre-treatment central nervous system evaluation, and 14 patients had central nervous system involvement at diagnosis (2.3% out of entire patients and 5.0% out of the 279 patients). For those patients, median follow-up duration was 38.2 months and some of them achieved long-term survival. Out of 581 patients who did not have central nervous system involvement at diagnosis, 26 patients underwent secondary central nervous system relapse with a median follow-up of 35 months, and the median time to central nervous system involvement was 10.4 months (range: 3.4–29.2). Serum lactate dehydrogenase > ×3 upper limit of normal range, the Eastern Cooperative Oncology Group performance status ≥ 2, and involvement of sinonasal tract or testis, were independent risk factors for central nervous system relapse in multivariate analysis. Our study suggests that enhanced stratification of serum lactate dehydrogenase according to the National Comprehensive Cancer Network-International Prognostic Index may contribute to better prediction for central nervous system relapse in patients with diffuse large B-cell lymphoma. This trial was registered at clinicaltrials.gov identifier: 01202448.

Cytogenetic and Molecular Failure at 12 Months will be the Optimal Time Point for BCR-ABL1 Tyrosine Kinase Domain Mutation Analysis in Patients with Chronic Myeloid Leukemia: The Analysis Based on 2013 European LeukemiaNet Recommendation

Abstract: CML-020 Cytogenetic and Molecular Failure at 12 Months will be the Optimal Time Point for BCR-ABL1 Tyrosine Kinase Domain Mutation Analysis in Patients with Chronic Myeloid Leukemia: The Analysis Based on 2013 European LeukemiaNet Recommendation Hee-Je Kim, Hea-Lyun Yoo, Won-Sik Lee, Hyeong-Joon Kim, Jee Hyun Kong, Yunsuk Choi, Young Rok Do, Jae-Yong Kwak, Sukjoong Oh, Sung Hyun Kim, Jeong-A. Kim, Dae Young Zang, Yeung-Chul Mun, Young-Woong Won, Sung-Eun Lee, Dong-Wook Kim Department of Hematology, Seoul St. Mary’s Hospital, The Catholic University of Korea; Department of Internal Medicine, Inje University College of Medicine, Inje University Busan Paik Hospital; Department of Hematology-Oncology, Chonnam National University Hwasun Hospital; Department of Hematology-Oncology, Wonju College of Medicine, Yonsei University; Department of Hematology, University of Ulsan College of Medicine, Ulsan University Hospital; Division of Hematology-Oncology, Keimyung University, School of Medicine, Keimyung University Hospital; Division of Hematology-Oncology, Chonbuk National University Medical School, Chonbuk National University Hospital; Division of Hematology-Oncology, Department of Internal Medicine, School of Medicine, Sungkyunkwan University, Kangbuk Samsung Hospital; Department of Internal Medicine, DongA University College of Medicine, Dong-A University Hospital; Department of Hematology, The Catholic University of Korea, St. Vincent’s Hospital; Department of Internal Medicine, Hallym University College of Medicine, Hallym University Hospital; Department of Hematology, School of Medicine, Ewha Womans University, Ehwa Womans University Hospital; Division of Hematology and Oncology, Department of Internal Medicine, Hanyang Univerysity College of Medicine, Hanyang University Guri Hospital CML-020 Cytogenetic and Molecular Failure at 12 Months will be the Optimal Time Point for BCR-ABL1 Tyrosine Kinase Domain Mutation Analysis in Patients with Chronic Myeloid Leukemia: The Analysis Based on 2013 European LeukemiaNet Recommendation Hee-Je Kim, Hea-Lyun Yoo, Won-Sik Lee, Hyeong-Joon Kim, Jee Hyun Kong, Yunsuk Choi, Young Rok Do, Jae-Yong Kwak, Sukjoong Oh, Sung Hyun Kim, Jeong-A. Kim, Dae Young Zang, Yeung-Chul Mun, Young-Woong Won, Sung-Eun Lee, Dong-Wook Kim Department of Hematology, Seoul St. Mary’s Hospital, The Catholic University of Korea; Department of Internal Medicine, Inje University College of Medicine, Inje University Busan Paik Hospital; Department of Hematology-Oncology, Chonnam National University Hwasun Hospital; Department of Hematology-Oncology, Wonju College of Medicine, Yonsei University; Department of Hematology, University of Ulsan College of Medicine, Ulsan University Hospital; Division of Hematology-Oncology, Keimyung University, School of Medicine, Keimyung University Hospital; Division of Hematology-Oncology, Chonbuk National University Medical School, Chonbuk National University Hospital; Division of Hematology-Oncology, Department of Internal Medicine, School of Medicine, Sungkyunkwan University, Kangbuk Samsung Hospital; Department of Internal Medicine, DongA University College of Medicine, Dong-A University Hospital; Department of Hematology, The Catholic University of Korea, St. Vincent’s Hospital; Department of Internal Medicine, Hallym University College of Medicine, Hallym University Hospital; Department of Hematology, School of Medicine, Ewha Womans University, Ehwa Womans University Hospital; Division of Hematology and Oncology, Department of Internal Medicine, Hanyang Univerysity College of Medicine, Hanyang University Guri Hospital