90 results on '"Kyoo-Hyung Lee"'
Search Results
2. Antileukemic Activity of Ypn-005, a CDK7 Inhibitor, Inducing Apoptosis through c-MYC and FLT3 Suppression in Acute Myeloid Leukemia
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Bon-Kwan Koo, Je-Hwan Lee, Eun-Ji Choi, Eun-Hye Hur, Ju Hyun Moon, Ji Yun Kim, Han-Seung Park, Yunsuk Choi, Jung-Hee Lee, Kyoo Hyung Lee, and Jinhwan Kim
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
3. Post-Transplantation Cyclophosphamide for Graft-Versus-Host Disease Prophylaxis in Allogeneic Hematopoietic Cell Transplantation for Higher-Risk Myelodysplastic Syndrome
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Han-Seung Park, Ji Min Woo, Young-Shin Lee, Je-Hwan Lee, Mijin Jeon, Jung-Hee Lee, Eun-Ji Choi, Hyeran Kang, Kyoo Hyung Lee, and Young-Ah Kang
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Oncology ,medicine.medical_specialty ,Hematopoietic cell ,business.industry ,Post transplantation cyclophosphamide ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Transplantation ,Graft-versus-host disease ,Internal medicine ,medicine ,business - Abstract
Introduction: Allogeneic hematopoietic cell transplantation is an only potentially curative option for patients with higher-risk myelodysplastic syndrome (MDS). Owing to the advances in treatment strategies including reduced intensity conditioning, graft-versus-host disease (GVHD) prevention and supportive care, more elderly patients or those with comorbidities can proceed to allogeneic HCT. However, the long-term survival rate following allogeneic HCT is reported to be less than 50%, and non-relapse mortality (NRM) rate is still high reaching upto 30%. In this study, we aimed to evaluate the feasibility of using post-transplantation cyclophosphamide (PTCy) as a GVHD prophylaxis in allogeneic HCT for higher-risk MDS patients. We also compared the post-transplantation outcomes of PTCy group and those of historical control who received HCT using anti-thymocyte globulin (ATG). Methods: Patients with higher-risk MDS or MDS/myeloproliferative neoplasm (MPN) with bone marrow blast ≥ 5% were included in this study. Higher-risk MDS was defined by MDS with International Prognostic Scoring System >1.0 or bone marrow blast ≥ 5% at any time points before HCT. Conditioning regimen consists of busulfan (4-days for patients aged Results: Ninety-two and 144 patients received allogeneic HCT using PTCy and ATG, respectively. The median overall survival were 47.9 and 44.0 months, respectively (P=.383). Cumulative incidence of total and grade II-IV acute GVHD in PTCy and ATG group were 19.6% vs. 37.5% (P=.002), and 2.6% vs. 21.7% (P Conclusion: Allogeneic HCT using PTCy as GVHD prophylaxis in higher-risk MDS seems feasible in terms of low rate of acute GVHD and relapse incidence. Disclosures Choi: Ingenium Therapeutics, Daejeon, Korea: Consultancy, Current holder of individual stocks in a privately-held company. Lee: Ingenium Therapeutics, Daejeon, Korea: Consultancy, Current holder of individual stocks in a privately-held company. Lee: Korean Society of Hematology: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board; AbbVie: Honoraria, Other: Advisory board.
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- 2021
4. First in Human (FIH) FLT3 and SYK Inhibitor HM43239 Shows Single Agent Activity in Patients (pts) with Relapsed or Refractory (R/R) FLT3 Mutated and Wild-Type Acute Myeloid Leukemia (AML)
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Hyun Jin Kim, Sung-Soo Yoon, Nora Lee, Chul Won Jung, Naval Daver, Jaeyeon Lee, Kyoo Hyung Lee, Brian A. Jonas, Martha Arellano, Seungjae Baek, and Jiyeon Yoon
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business.industry ,Immunology ,Wild type ,Myeloid leukemia ,Syk ,Cell Biology ,Hematology ,First in human ,Biochemistry ,Refractory ,Cancer research ,Medicine ,In patient ,Single agent ,business - Abstract
Background: HM43239 is a novel FMS-like tyrosine kinase 3 (FLT3) inhibitor with potent in vitro and in vivo activity against both FLT3 mutated and wild-type AML. Preclinically HM43239 was highly active against FLT3 internal tandem duplication (ITD) mutated as well as resistance-conferring D835 and gatekeeper (F691) tyrosine kinase domain (TKD) mutated AML cell lines and xenograft models (AACR2021 abstract 1257). In addition to FLT3, HM43239 inhibits phosphorylation of spleen tyrosine kinase (SYK) known to be highly activated in AML and associated with resistance to FLT3 targeted therapy. We report data from an ongoing Phase 1/2 dose escalation and expansion FIH study assessing the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of HM43239 in pts with R/R AML. Methods: A phase 1/2 trial was conducted to evaluate HM43239 in pts with R/R AML who had received at least 1 prior line of therapy, including ≥ 1 prior FLT3 inhibitors (FLT3i). Pts with or without a FLT3 mutation (FLT3m) received HM43239 orally once daily until unacceptable toxicity or no clinical benefit (each cycle of ~28 days). Doses 20 to 160 mg had been evaluated at the time of this abstract. The dose escalation was initiated with an accelerated titration design followed by a 3+3 design. The 3+3 design kicked in after the first instance of a dose limiting toxicity (DLT) or moderate toxicity (MT, a grade 2 non-hematologic adverse event (AE) judged by the investigator to be at least possibly related to study drug) occurred. Parallel backfill expansion of cohorts deemed safe were initiated based on the observed safety and efficacy in the dose-escalation. AEs were graded per NCI-CTCAE (v4.03). Responses were evaluable according to the international working group (IWG) AML criteria including complete remission (CR) and composite CR (CRc). PK was examined after single and multiple dose (15 or 17 days) of 20 to 160 mg. Inhibition of FLT3 phosphorylation (pFLT3) was evaluated by a plasma inhibitory activity (PIA) assay and correlated with exposure levels. Results: Twenty-eight pts were enrolled at multiple international centers between March 2019 and June 2021: 13 in the dose escalation cohorts 20 - 160 mg and 15 in the dose expansion cohort at 80 mg. Patient characteristics are shown in Table 1. Median number of prior therapies for AML in this R/R pts was 2 (range, 1-7). Ten pts (36%) had FLT3m, 16 pts (57%) had FLT3 wild-type (FLTwt), and 2 pts (7%) were FLT3 unknown at enrollment. Most frequently reported FLT3m was ITD (21%) followed by TKD (11%), and ITD/TKD (4%). After 1 pt in the 80 mg dose escalation cohort showed a MT (Grade 3 nausea), the accelerated titration design was switched to the 3+3 design for 80 mg and higher doses. The most common drug related treatment-emergent adverse events (TEAEs) were diarrhea (14%), nausea (7%), vomiting (7%) and alanine aminotransferase increased (7%), and no drug related > Grade 3 TEAEs were observed to date. Five of 28 pts treated at all dose levels achieved CRc (17.9%) (Table 2). Best response was IWG CR in 4 pts and IWG CRi in 1 pt. All 5 CRc pts were treated at the 80 mg dose (n= 19) resulting in CRc of 26.3% at the 80 mg dose. Of 8 FLT3m pts at 80 mg, CRc was achieved in 3 pts (37.5%) and one had received prior FLT3i, gilteritinib. Of 11 FLT3wt pts at 80 mg, CRc was achieved in 2 pts (18%), including a relapsed TP53m AML who achieved CR and remained on study for 12 months before progressing. Among the remaining 4 CRc pts, three proceeded to hematopoietic stem cell transplantation (HSCT) remaining alive and in remission post HSCT at this time, and one remains in CR in Cycle 3 (Fig 1). The plasma concentration showed dose-dependent increase after single administration of 20 to 160 mg. After 17 days of treatment, steady-state was reached and PIA assay showed dose-dependent inhibition of pFLT3 with up to 90% at the dose levels ≥ 80 mg. Conclusions: HM43239 a preclinically potent FLT3 and SYK inhibitor showed a favorable safety profile with only mild AEs and no DLTs in this ongoing Phase 1/2 study. At 80 mg dose, HM43239 demonstrates clinical activity in both FLT3m (including a prior gilteritinib failure pt) and FLT3wt AML (including >1 year CR without HSCT in a relapsed TP53m AML). We continue to further evaluate doses above 80 mg to determine the optimal recommended Phase 2 Dose (RP2D). The dose escalation cohort of 160 mg and the dose expansion cohort of 120 mg are currently enrolling and updated response, safety, and PK/PD data will be presented. NCT03850574. Figure 1 Figure 1. Disclosures Daver: Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Trovagene: Consultancy, Research Funding; Hanmi: Research Funding; Genentech: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Novimmune: Research Funding; Glycomimetics: Research Funding; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Lee: Ingenium Therapeutics, Daejeon, Korea: Consultancy, Current holder of individual stocks in a privately-held company. Arellano: Syndax Pharmaceuticals, Inc: Consultancy; KITE Pharma, Inc: Consultancy. Yoon: Hanmi Pharmaceutical: Current Employment. Lee: Hanmi Pharmaceutical: Current Employment. Kim: Hanmi Pharmaceutical: Current Employment. Lee: Hanmi Pharmaceutical: Current Employment. Jonas: AbbVie, BMS, Genentech, GlycoMimetics, Jazz, Pfizer, Takeda, Treadwell: Consultancy; 47, AbbVie, Accelerated Medical Diagnostics, Amgen, AROG, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche, Forma, Genentech/Roche, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, Treadwell: Research Funding; AbbVie: Other: Travel reimbursement. Baek: Hanmi Pharmaceutical: Current Employment.
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- 2021
5. Similar Survival and Genetic Features between Clonal Cytopenia of Undetermined Significance and Lower-Risk Myelodysplastic Syndrome
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Han-Seung Park, Young-Uk Cho, Eun-Ji Choi, Sang-Hyun Hwang, Seongsoo Jang, Kyoo Hyung Lee, Chan-Jeoung Park, Je-Hwan Lee, and Jung-Hee Lee
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Oncology ,medicine.medical_specialty ,Cytopenia ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Lower risk ,Biochemistry ,hemic and lymphatic diseases ,Internal medicine ,medicine ,business - Abstract
Background Idiopathic cytopenia of undetermined significance (ICUS) is characterized by a persistent and clinically significant cytopenias which does not meet the diagnostic criteria for myelodysplastic syndrome (MDS). In some patients with ICUS, disease evolution to MDS or acute myeloid leukemia after variable periods of time was observed in several studies. However, the incidence and predictive factors of progression as well as management guidelines for ICUS patients are not well established. We aimed to identify the clinical and genetic characteristics of ICUS in comparison with lower-risk MDS for understanding the pathophysiologic features and providing guidance for treating physicians. Methods We performed targeted deep sequencing including 61 myeloid neoplasm-related genes with a MiSeqDx sequencer (Illumina) using bone marrow (BM) samples obtained from the patients with ICUS (n=139) and MDS (n=226) between May 2009 and December 2019. The cut-off level of variant allele frequency (VAF) was set to 2.0% of mutant allele reads. Cloncal cytopenia of undetermined significance (CCUS) was defined as ICUS with ≥ 2% VAF of mutations and lower-risk MDS was defined as MDS with revised international prognostic scoring system ≤3.5. Results When we compared the overall survival (OS) of the patients according to the disease subtypes, OS of CCUS (77.0% at 5-year) was significantly better than that of higher-risk MDS (41.0%, P Conclusion In our study, CCUS and lower-risk MDS showed similar OS which was significantly better than higher-risk MDS and worse than non-clonal ICUS. The clinical and mutational characteristics were also similar except for the degree of anemia and the SF3B1 and STAT3 mutation. Our findings suggest that the patients with CCUS may be regarded and treated as the lower-risk MDS despite a lack of significant dysplasia or MDS-associated definitive chromosomal abnormality. Disclosures Choi: Ingenium Therapeutics, Daejeon, Korea: Consultancy, Current holder of individual stocks in a privately-held company. Lee: Ingenium Therapeutics, Daejeon, Korea: Consultancy, Current holder of individual stocks in a privately-held company. Lee: Korean Society of Hematology: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Other: Advisory board; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board.
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- 2021
6. Machine Learning-Based Approach to Predict Survival after Allogeneic Hematopoietic Cell Transplantation in Hematologic Malignancies
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Je-Hwan Lee, Han-Seung Park, Eun-Ji Choi, Jung-Hee Lee, Kyoo Hyung Lee, Ji Min Woo, Young-Shin Lee, Hyeran Kang, Young-Ah Kang, Mijin Jeon, and Jun-Hong Park
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Acute leukemia ,Receiver operating characteristic ,business.industry ,Donor selection ,Immunology ,Cell Biology ,Hematology ,Logistic regression ,medicine.disease ,Machine learning ,computer.software_genre ,Biochemistry ,Confidence interval ,Transplantation ,Medicine ,Artificial intelligence ,business ,computer ,Myeloproliferative neoplasm ,Multiple myeloma - Abstract
Background Allogeneic hematopoietic cell transplantation (HCT) has been more widely applicable to the patients with hematologic malignancies owing to the increased donor availability, advances in conditioning regimen, prevention of transplantation-related toxicities, and general supportive care. However, there is no comprehensive and uniform approach for decision making which incorporates transplantation-related factors including patients and donor selection, conditioning intensity, or prevention of graft-versus-host disease (GVHD). In this regard, we aimed to establish and validate a machine learning-based predictive model for survival after allogeneic HCT in hematologic malignancies. Method Data from 2,011 patients with hematologic malignancies (1,464 acute leukemia, 296 myelodysplastic syndrome, 100 chronic myeloid leukemia, 45 myeloproliferative neoplasm, 85 lymphoma, and 21 multiple myeloma) who received allogeneic HCT between December 1993 and December 2019 at the Asan Medical Center were retrospectively analyzed. Results The median overall and event-free survival of total patients were 4.2 year (95% confidence interval [CI], 2.9-5.4) and 1.5 year (95% CI, 1.1-1.8), respectively. To predict post-transplantation survival, the patients were classified into "survived more than 5 years" and "died before 5 years". Among four major machine learning models (random forest [RF], support vector machine, logistic regression, and feed forward neural network), we selected RF method according to the predictive power of each algorithm. Using the RF machine learning algorithm, we developed a post-transplantation survival predicting model with the training cohort of 1,408 patients (70%) and tested it with the validation cohort of 603 patients (30%). Of >200 variables, 33 were selected using recursive feature elimination, and the estimated area under the receiver operator characteristic curve and accuracy of the model was 0.812 and 0.73, respectively. We then evaluated the robustness of predictive power of the model using 10-fold cross-validation in validation cohort. In addition, risk scores were calculated from each patient in the validation cohort, and there was an agreement between the estimated predicted risk and observed risk. Conclusion In conclusion, the machine learning-based prediction model seems feasible assuming post-transplantation survival outcomes in hematologic malignancies. Our findings could be helpful for clinicians to select more appropriate donor in terms of age or type of human leukocyte antigen mismatch, conditioning regimen, and GVHD prophylaxis. Disclosures Lee: Astellas: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Lee:Hanmi: Research Funding.
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- 2020
7. HM43239, a Novel Small Molecule Inhibitor of FLT3, in Acute Myeloid Leukemia (AML) with and without FMS-like Tyrosine Kinase 3 (FLT3) Mutations: Phase 1/2 Study
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Yoon Sung Soo, Naval Daver, Song Kim, Kyoo Hyung Lee, Martha Arellano, Chul Won Jung, Brian A. Jonas, Jiyeon Yoon, Inhwan Bae, Sooa Jung, and Young Su Noh
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medicine.medical_specialty ,business.industry ,Clinical study design ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Clinical trial ,Tolerability ,Family medicine ,Fms-Like Tyrosine Kinase 3 ,Flt3 mutation ,Health care ,Cohort ,Clinical endpoint ,Medicine ,business ,health care economics and organizations - Abstract
Background: FLT3 mutations, found in ~30% of patients with AML, and are associated with a poor prognosis. HM43239 is a novel FLT3 inhibitor that potently inhibits not only FLT3 mutants, including ITD and TKD mutants and FLT3 wild type but also spleen tyrosine kinase (SYK). Its dual inhibition of both FLT3 and SYK may activity in AML. In preclinical studies, HM43239 showed more potent activity than Gilteritinib in FLT3-WT/ITD heterozygous MOLM-13/-14 AML cell models. Furthermore, HM43239 showed potent antileukemia activity in xenograft models of FLT3-ITD/F691L cell lines harboring double mutations of ITD/TKD, without any body weight loss or significant toxicity. These results indicate that HM43239 may be useful in the treatment of AML patients with FLT3-ITD and/or -TKD mutation, including patients with gilteritinib resistant mutations such as F691L. Herein, we present a clinical trial design to assess the potential clinical activity and safety of HM43239 in patients with AML. This phase I/II clinical trial (NCT03850574) is in clinical development in the United States and Korea to access the overall safety and efficacy of HM43239 in AML. Trial Design: This is an ongoing, open-label, multicenter, first in human phase I/II trial enrolling adult FLT3 mutated and FLT3 wild-type patients with AML who have relapsed or refractory disease after at least one prior line of therapy, what can include prior FLT3 inhibitors such as gilteritinib, midostaurin. Patients are treated with HM43239 once daily (QD) in 28-day cycles, except for the first 30-day cycle, which includes a single PK sampling period. This trial comprises two parts: dose-escalation (Part A) and dose expansion (Part B). During dose escalation, the study follows an accelerated titration design, with around 50% dose increments and 1 patient per dose level. Accelerated titration will continue until 1 patient experiences dose-limiting toxicity (DLT) or moderate toxicity (MT), drug-related grade 2 adverse event (except for hematologic toxicities), at any dose level, after which, a 3 + 3 dose-escalation design will be used. If a patient achieves a clinical response at any dose level in the escalation cohort, an expansion cohort will be open at that dose level. Based on the evaluation of DLTs and composite complete remissions (CRc) from the dose-escalation cohorts, additional subjects may be recruited in the expansion cohort at each dose level selected for expansion. If no CRc is achieved in 6 subjects or less than 2 composite CRs are achieved in 12 subjects who complete 2 treatment cycles that dose level will stop further enrollment. Subjects with FLT3 wild-type will be enrolled to both escalation and expansion cohorts, however, at least 10 subjects with FLT3 mutations (ITD or activating point mutations such as D835Y, D835V, I836) should be enrolled to each dose level selected for expansion (including the subjects from the dose-escalation cohort). Blood samples are collected for pharmacokinetics (PK) & pharmacodynamics (PD) evaluation and for exploratory biomarker analysis in both cohorts. A 2-parameter Bayesian logistic regression will be used to model the dose-toxicity relationship on DLT in dose-escalation and expansion parts and the estimated DLT rate will be provided as a supportive reference for dose-escalation procedure and safety monitoring. The primary endpoint is the assessment of safety, tolerability and PK to determine the recommended phase 2 dose (RP2D). Secondary endpoints include best response rate, duration of response, event free survival, overall survival, cumulative incidence of relapse. PK-PD relationships and PD evaluated by plasma inhibitory assay are exploratory endpoints. The trial was initiated in Jan 2019 and patients have been evaluated since May 2019. Dose level 1 (20 mg) and 2 (40mg) were completed without any DLTs. In Dose level 3 (80mg), one patient experienced MT, the design was changed from accelerated titration design to 3+3 design. Three patients (one FLT3 mutated) were enrolled, including an ongoing FLT3 wild-type patient (currently in cycle 5) with relapsed AML post-stem cell transplant who had prior chemotherapy and achieved CRi and maintains 0% marrow blasts. The enrollment to next dose level 4 (120mg) initiated in June 2020 and subjects have been enrolled. This study is currently recruiting patients at multiple sites in the Republic of Korea and the USA. Clinical trial information: NCT03850574. Disclosures Daver: Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lee:Hanmi: Research Funding. Jung:Hanmi: Research Funding. Soo:Hanmi: Research Funding. Arellano:Cephalon Oncology: Research Funding; Hanmi: Research Funding; Gilead Sciences, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jonas:LP Therapeutics: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Sigma Tau: Research Funding; Celgene: Consultancy, Research Funding; AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Amgen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GlycoMimetics: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Genentech/Roche: Research Funding; Hanmi: Research Funding; Incyte: Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Tolero: Consultancy; Treadwell: Consultancy; Forty Seven: Research Funding; Accelerated Medical Diagnostics: Research Funding; AROG: Research Funding; Daiichi Sankyo: Research Funding; F. Hoffmann-La Roche: Research Funding; Forma: Research Funding. Yoon:Hanmi: Current Employment. Jung:Hanmi: Current Employment. Noh:Hanmi: Current Employment. Bae:Hanmi: Current Employment. Kim:Hanmi: Current Employment.
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- 2020
8. DDX41 mutation in Patients with Idiopathic Cytopenia of Undetermined Significance, Myelodysplastic Syndrome, and Acute Myeloid Leukemia
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Je-Hwan Lee, Nayoung Kim, Eun-Hye Hur, Han-Seung Park, Seongsoo Jang, Chan-Jeoung Park, Eun-Ji Choi, Hee Jeong Ouk, Young-Uk Cho, Jung-Hee Lee, and Kyoo Hyung Lee
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Oncology ,Cytopenia ,Mutation ,medicine.medical_specialty ,Myeloid ,business.industry ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,medicine.disease_cause ,Biochemistry ,Germline ,medicine.anatomical_structure ,Germline mutation ,International Prognostic Scoring System ,hemic and lymphatic diseases ,Internal medicine ,medicine ,business - Abstract
Background Following the advances in genetic tests, including next-generation sequencing, there have been new insights into hereditary hematopoietic malignancies. The germline mutation in DDX41 was included in a new category, myeloid neoplasms with germline predisposition, of the updated 2016 WHO classification. Based on the reported data to date, there seem to be racial differences in the mutation variants of DDX41 gene, which were found in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Idiopathic cytopenia of undetermined significance (ICUS) is known to be a precursor lesion of MDS, but the DDX41 mutations have not been evaluated in patients with ICUS. In this study, we aimed to reveal the incidence, genetic characteristics, and clinical features of the DDX41 mutations in patients with ICUS, MDS, and AML. Methods We performed targeted deep sequencing of 141 genes with a MiSeqDx sequencer (Illumina) using bone marrow (BM) samples obtained from the patients with ICUS (n=77), MDS (n=175), and AML (n=148) between May 2009 and June 2019. ICUS was defined by the proposed criteria of 2007 Consensus Group. The cut-off level of variant allele frequency (VAF) was set to 2.0% of mutant allele reads. We divided ICUS into clonal cytopenia of undetermined significance (CCUS), which was defined as ICUS with ≥ 2% VAF of somatic mutations of myeloid malignancy-associated genes and non-CCUS. Results Overall, DDX41 mutations were detected in 6 (7.8%) of 77 ICUS, 19 (10.9%) of 175 MDS, and 8 (5.4%) of 148 AML patients. Thirty-eight (49.4%) of 77 ICUS patients had CCUS. Of 6 DDX41 mutated patients with CCUS, 5 showed biallelic mutations with the median VAF of 44.7% (range, 29.3−50.0) and 10.2% (range, 3.3−25.4), indicating that one germline and one somatic mutation exists. Of 175 MDS patients, 78 were categorized into lower-risk MDS (revised international prognostic scoring system [IPSS-R] < 3.5) and 97 into higher-risk MDS (IPSS-R ≥ 3.5), and DDX41 mutations were identified in 6 (7.7%) of 78 lower-risk MDS and 13 (13.4%) of 97 higher-risk MDS patients. Interestingly, biallelic mutations were found in 16 of 18 DDX41-mutated MDS patients with the median VAF of 47.75% (range, 43.4−55.6) and 13.8% (range, 2.7−35.8). In contrast, only one of 8 DDX41-mutated AML patients had biallelic mutation. Patients with DDX41 mutations typically showed hypocellular marrow (median BM cellularity, 30%; range, 5−95) with significant neutropenia (median neutrophil counts, 607/μL; range, 142−1675), male predominance (29/33, 87.9%), and relatively older age (median age, 64 years; range, 41−79) at diagnosis. In addition, we found novel mutation locations, which were different between presumed germline and somatic variants: V152G in germline, and T227M in somatic (Table 2). During a median follow-up duration of 2.9 years, 1 of 6 ICUS patients progressed to MDS-EB-1 after 17.3 months and 1 to non-severe aplastic anemia after 51.3 months. Conclusion Our data show that a significant proportion of ICUS, MDS, and AML patients had DDX41 mutations, many of which are presumably germline. These findings suggest that careful consideration of the predisposing germline mutation is important when selecting a familial donor for allogeneic HCT. We also found novel mutation locations of DDX41 gene which were different between somatic and germline variants. Further studies are warranted to define the clinical and molecular characteristics of DDX41 mutations and therapeutic implications in myeloid neoplasms. Disclosures No relevant conflicts of interest to declare.
- Published
- 2019
9. Mutational Characteristics and Changing Pattern from Idiopathic Cytopenia of Undetermined Significance to High-Risk Myelodysplastic Syndrome Stratified By IPSS-R
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Je-Hwan Lee, Eun-Ji Choi, Han-Seung Park, Eun-Hye Hur, Chan-Jeoung Park, Nayoung Kim, Jung-Hee Lee, Hee Jeong Ouk, Young-Uk Cho, Kyoo-Hyung Lee, and Seongsoo Jang
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Oncology ,Cytopenia ,medicine.medical_specialty ,Mutation ,IDH1 ,business.industry ,Immunology ,Disease progression ,Cell Biology ,Hematology ,Disease ,medicine.disease ,medicine.disease_cause ,Biochemistry ,ETV6 ,International Prognostic Scoring System ,hemic and lymphatic diseases ,Internal medicine ,medicine ,KRAS ,business - Abstract
Background: Unexplained cytopenia comprises a spectrum of hematological diseases from idiopathic cytopenia of undetermined significance (ICUS) to myelodysplastic syndrome (MDS). Revised International Prognostic Scoring System (IPSS-R) is the standard tool to assess risk in MDS. Here, we investigated the occurrence, characteristics, and changing pattern of mutations in patients with ICUS and MDS stratified by IPSS-R score. Methods: A total of 211 patients were enrolled: 73 with ICUS and 138 with MDS. We analyzed the sequencing data of a targeted gene panel assay covering 141 genes using the MiSeqDx platform (Illumina). The lower limit of variant allele frequency (VAF) was set to 2.0% of mutant allele reads. Bone marrow components were assessed for the revised diagnosis according to the 2016 WHO classification. Lower-risk (LR) MDS was defined as those cases with very low- or low-risk MDS according to the IPSS-R. Higher-risk (HR) MDS was defined as those cases with high- or very high-risk MDS according to the IPSS-R. Results: Patients with ICUS were classified as very low-risk (39.7%), low-risk (54.8%), and intermediate-risk (5.5%) according to the IPSS-R. Patients with MDS were classified as LR (35.5%), intermediate-risk (30.4%), and HR (34.1%). In the ICUS, 28 (38.4%) patients carried at least one mutation in the recurrently mutated genes in MDS (MDS mutation). The most commonly mutated genes were DNMT3A (11.0%), followed by TET2 (9.6%), BCOR (4.1%), and U2AF1, SRSF2, IDH1 and ETV6 (2.7% for each). IPSS-R classification was not associated with mutational VAF and the number of mutations in ICUS. In the 49 LR MDS, 28 (57.1%) patients carried at least one MDS mutation. The most commonly mutated genes were SF3B1 (20.4%), followed by TET2 (12.2%), U2AF1 (10.2%), DNMT3A (10.2%), ASXL1 (10.2%), and BCOR (6.1%). Higher VAF and number of mutations were observed in LR MDS compared to ICUS patients. In the 42 intermediate-risk MDS, 27 (64.3%) patients carried at least one MDS mutation. The most commonly mutated genes were ASXL1 (23.8%), followed by TET2 (21.4%), RUNX1 (16.7%), U2AF1 (14.3%), DNMT3A (14.3%), SF3B1 (9.5%), and SRSF2, BCOR, STAG2 and CBL (7.1% for each). In the 47 HR MDS, 36 (76.6%) patients carried at least one MDS mutation. The most commonly mutated genes were TET2 (25.5%), followed by DNMT3A (14.9%), TP53 (14.9%), RUNX1 (12.8%), U2AF1 (10.6%), ASXL1 (10.6%), and SRSF2 and KRAS (6.4% for each). As the disease progressed, VAF and number of the MDS mutations gradually increased, and mutations involving RNA splicing, histone modification, transcription factor or p53 pathway had a trend for increasing frequency. Specifically, ASXL1, TP53, and RUNX1 mutations were the most striking features in patients with advanced stage of the disease. Cohesin mutations were not detected in ICUS, whereas these mutations were detected at a relatively high frequency in HR MDS. Our data were summarized in Table 1. Conclusions: We demonstrate that on disease progression, MDS mutations are increased in number as well as are expanded in size. Furthermore, a subset of mutations tends to be enriched for intermediate- to HR MDS. The results of this study can aid both diagnostic and prognostic stratification in patients with unexpected cytopenia. In particular, characterization of MDS mutations can be useful in refining bone marrow diagnosis in challenging situations such as distinguishing LR MDS from ICUS. Disclosures No relevant conflicts of interest to declare.
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- 2019
10. Clinical Implications of Copy Number Variant Detection from Panel-Based Next-Generation Sequencing Data in Myelodysplastic Syndrome
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Seon-Hee Yim, Kyoo Hyung Lee, Yong-Rim Kwon, Eun-Ji Choi, Je-Hwan Lee, Sug Hyung Lee, Seung-Hyun Jung, Young-Woo Jeon, Yeun-Jun Chung, Hye-Jung Kim, Yoo-Jin Kim, and Eun-Hye Hur
- Subjects
Univariate analysis ,Immunology ,Neutrophil collagenase ,Cell Biology ,Hematology ,Computational biology ,Biology ,Biochemistry ,DNA sequencing ,Log-rank test ,Copy Number Polymorphism ,Copy-number variation ,Bone marrow specimen ,Protein p53 - Abstract
Some of the recurrently occurring somatic mutations are known to be diagnostic or prognostic in myelodysplastic syndrome (MDS). Targeted gene capture and next-generation sequencing (NGS) has rapidly become routine clinical tools to detect the somatic mutations in patients with MDS. Copy number variants (CNVs) may have additional clinical significance in MDS. Chromosomal microarray analysis is a standard technique for genome-wide CNV detection, but multiple testing strategies require high costs and time. Recent advancements in NGS technologies have developed more cost-effective and rapid methods to allow simultaneous identification of targeted CNVs as well as somatic mutations using the same panel-based NGS data. In this study, we investigated whether the detection of CNVs using the targeted NGS data provided an additional value other than the clinical implications of somatic mutations. We performed targeted deep sequencing analysis on bone marrow samples obtained from 266 patients with MDS using an MDS panel targeting 28 well-known MDS-related genes (NRAS, DNMT3A, SF3B1, IDH1, TET2, NPM1, LAMB4, EZH2, JAK2, CBL, ETV6, KRAS, FLT3, IDH2, PRPF8, TP53, NF1, SRSF2, SETBP1, DNMT1, ASXL1, RUNX1, U2AF1, ZRSR2, ATRX, STAG2, MMP8, and ARID2). Sequencing libraries were generated using the AmpliSeq Library Kit 2.0 (Life Technologies, Carlsbad, CA) and the MDS panel was then sequenced using the Ion Torrent Proton system (Life Technologies) according to the manufacturer's instructions. The multiscale reference module and Rank Segmentation statistical algorithm in NEXUS software v9.0 (Biodiscovery) were used to define the CNVs for each sample. Overall survival (OS) and acute myeloid leukemia (AML)-free survival (AFS) were estimated from the date of MDS diagnosis to death or AML progression using the Kaplan-Meier method, and the differences in survival were compared using the log-rank test (for univariate analysis) and the Cox proportional hazards model (for multivariate analysis). Overall, 215 patients (80.8%) carried at least one somatic mutations, and 67 (25.2%) had one or more CNVs. The number of mutated genes per patient ranged from 0 to 6, and the number of genes with CNVs per patient ranged from 0 to 10. Of 51 patients who did not have somatic mutations, 12 (23.5%) had the targeted CNVs. The mutated genes in more than 10% of patients were 8: U2AF1 (21.8%), TET2 (17.7%), ASXL1 (13.5%), TP53 (13.2%), SETBP1 (12.8%), NF1 (10.9%), SF3B1 (10.5%), and RUNX1 (10.5%). The genes with CNVs detected in 10 or more patients were 5: EZH2 (loss in 7q, 6.8%), KRAS (gain and loss in 12p, 5.3%), ASXL1 (gain and loss in 20q, 4.5%), LAMB4 (loss in 7q, 3.8%), and RUNX1 (gain and loss in 21q, 3.8%). Interestingly, all five patients with TP53 deletion exhibited TP53 mutation as well, suggesting a bi-allelic alteration (mutation + copy loss). The higher number of genes with CNVs per patient were significantly associated with inferior OS (P Our study suggests that simultaneous detection of targeted CNVs as well as somatic mutations using the same panel-based NGS data add clinically useful information on the prognosis of MDS patients. Disclosures No relevant conflicts of interest to declare.
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- 2019
11. Long-Term Outcomes of Chronic Myeloid Leukemia Patients Who Lost Undetectable Molecular Residual Disease (UMRD) after Imatinib Discontinuation: Korean Imatinib Discontinuation Study (KIDS)
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Young Rok Do, Yunsuk Choi, Kyoo Hyung Lee, Yeung-Chul Mun, Dong-Wook Kim, Sung-Hyun Kim, Dae Young Zang, Jae-Yong Kwak, Sung-Eun Lee, Jinny Park, Hyeoung-Joon Kim, Won Sik Lee, Jeong-A Kim, Jihyun Kwon, Sukjoong Oh, Myung Hee Chang, and Joon Seong Park
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Oncology ,medicine.medical_specialty ,Measles-Mumps-Rubella Vaccine ,business.industry ,Immunology ,Ponatinib ,Myeloid leukemia ,Imatinib ,Cell Biology ,Hematology ,Disease ,Biochemistry ,Discontinuation ,Dasatinib ,chemistry.chemical_compound ,Imatinib mesylate ,chemistry ,Internal medicine ,Medicine ,business ,medicine.drug - Abstract
Background The recent discontinuation clinical trials have demonstrated that IM discontinuation can be employed based on clinical study in patients who had enough IM therapy and undetectable molecular residual disease (UMRD) durations prior to IM discontinuation. Moreover, treatment rechallenge in patients with molecular recurrence lead a second deep molecular response, suggesting that IM discontinuation is safe. However, the issues on the definition of molecular relapse requiring treatment resumption and the occurrence of late relapse with a long-term follow-up after IM discontinuation are important. Therefore, here we analyzed the long-term follow-up results of the patients who lost UMRD after IM discontinuation Methods CP CML patients who were treated with IM for more than 3 years and had undetectable levels of BCR-ABL1 transcripts determined by quantitative reverse transcriptase polymerase chain reaction (PCR) for at least 2 years were eligible for KID study and in cases of MMR loss after 2 consecutive assessments, IM treatment was re-introduced. After IM resumption for MMR loss, the molecular response was evaluated every month until MMR was re-achieved and every 3 months thereafter. The second stop was permitted in the patients who were in second UMRD for at least 2 years. Results Between October 2010 and June 2015, a total of 126 patients (70 females, 56 males) were enrolled on KID Study, with a median age of 47 years (range, 18-82), the percentages of patients with low, intermediate and high Sokal risk scores were 33%, 25% and 15%, respectively with unknown Sokal risk scores in 27%. And the median time on IM therapy and the median duration of sustained UMRD prior to discontinuation were 83 months (range, 32-141) and 41 months (range, 22-131), respectively. After a median follow-up of 62.6 months (range, 4.9-100.8 months) after IM discontinuation, 83 patients (65.9%) lost UMRD. Among them, 56 (67.5%) patients lost MMR in 2 consecutive analyses. The other 27 (32.5%) patients who lost UMRD but not MMR exhibited different patterns of BCR-ABL1 kinetics: 8 patients spontaneously re-achieved UMRD after a median time of 2.8 months (range, 0.9-3.0 months), and 19 patient showed fluctuation of BCR-ABL1 transcript under the level of 0.1% on IS for a median 19 months (range, 3-34), and then spontaneously returned and maintained UMRD for a median 31 months (range, 2-64). Of 73 patients who lost MR4.0, the rate of MMR loss was 76.7%. Out of 56 patients with molecular relapse, 54 patients (except two patients who restart radotinib) were re-treated with IM, all patients (except one patient lost follow-up) re-achieved MMR at a median of 1.9 months (range, 0.0 - 5.4 months) after resuming treatment. Among them, two patients who re-achieving of MMR after resuming IM therapy lost MMR again; One patient who relapsed at 53.2 months after IM discontinuation, despite re-achieving MMR 1.4 later after IM restarting, suddenly progressed to blast crisis at 6 months after restarting IM and in spite of switching to dasatinib and ponatinib, she died. Another patient lost MMR at 7.4 months after IM discontinuation and re-achieved MMR 1.7 later after IM restarting, but progressed to AP on the assessment 32 months later. The patient switched to dasatinib and lost follow-up. Among the patients who maintained a second UMRD for at least 2 years after IM resumption, 23 patients entered into a second IM stop. With a median follow-up of 29.5 months (range, 9-63 months) since second IM stop, 15/23 patients (65%) lost MMR after a median 2.9 months (range, 1.8-30.7 months), which was similar to those of the first IM discontinuation [median 3.7 (range, 1.8-20.8 months)]. The patients who lost MMR were retreated with IM for a median of 24.5 months (range, 1.2-49.7 months); 14 patients re-achieved MMR and one patient was in therapy for 1.2 months. Conclusions Our results showed that 67.5% and 76.7% of patients who lost UMRD and MR4.0, respectively resulted in MMR loss, and the other patients were below MMR without re-treatment, suggesting loss of MMR can be chosen for treatment re-challenge. Overall, IM discontinuation could be applied with approximately 55% of probability of sustained MMR in the long term. In addition, we demonstrated that a second attempt might be possible. Further studies on the predictors to select patients for a trial of second stop are warranted. Disclosures Kim: Il-Yang co.: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; BMS: Research Funding; Novartis: Research Funding.
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- 2019
12. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia
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Dae-Young, Kim, Young-Don, Joo, Sung-Nam, Lim, Sung-Doo, Kim, Jung-Hee, Lee, Je-Hwan, Lee, Dong Hwan Dennis, Kim, Kihyun, Kim, Chul Won, Jung, Inho, Kim, Sung-Soo, Yoon, Seonyang, Park, Jae-Sook, Ahn, Deok-Hwan, Yang, Je-Jung, Lee, Ho-Sup, Lee, Yang Soo, Kim, Yeung-Chul, Mun, Hawk, Kim, Jae Hoo, Park, Joon Ho, Moon, Sang Kyun, Sohn, Sang Min, Lee, Won Sik, Lee, Kyoung Ha, Kim, Jong-Ho, Won, Myung Soo, Hyun, Jinny, Park, Jae Hoon, Lee, Ho-Jin, Shin, Joo-Seop, Chung, Hyewon, Lee, Hyeon-Seok, Eom, Gyeong Won, Lee, Young-Uk, Cho, Seongsoo, Jang, Chan-Jeoung, Park, Hyun-Sook, Chi, Kyoo-Hyung, Lee, and Jae-Cheol, Jo
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Vincristine ,Neoplasm, Residual ,Adolescent ,Prednisolone ,medicine.medical_treatment ,Immunology ,Hematopoietic stem cell transplantation ,Biochemistry ,Drug Administration Schedule ,Recurrence ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Transplantation, Homologous ,Medicine ,Prospective Studies ,Prospective cohort study ,Survival analysis ,Aged ,business.industry ,Daunorubicin ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Cell Biology ,Hematology ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Survival Analysis ,Minimal residual disease ,Transplantation ,Pyrimidines ,Treatment Outcome ,Nilotinib ,Female ,business ,medicine.drug - Abstract
We investigated the effects of nilotinib plus multiagent chemotherapy, followed by consolidation/maintenance or allogeneic hematopoietic cell transplantation (allo-HCT) for adult patients with newly diagnosed Philadelphia-positive (Ph-pos) acute lymphoblastic leukemia (ALL). Study subjects received induction treatment that comprised concurrent vincristine, daunorubicin, prednisolone, and nilotinib. After achieving complete hematologic remission (HCR), subjects received either 5 courses of consolidation, followed by 2-year maintenance with nilotinib, or allo-HCT. Minimal residual disease (MRD) was assessed at HCR, and every 3 months thereafter. The molecular responses (MRs) were defined as MR3 for BCR-ABL1/G6PDH ratios ≤10(-3) and MR5 for ratios
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- 2015
13. Pilot Prospective Phase II Study of Nilotinib Combined with Chemotherapy for Myeloid Blastic Phase of Chronic Myeloid Leukemia or Acute Myeloid Leukemia with BCR/ABL1
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Hawk Kim, Won-Sik Lee, Yunsuk Choi, Kyoo-Hyung Lee, Jeong Yeal Ahn, Sung-Soo Yoon, Sang Kyun Sohn, and Jee Hyun Kong
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0301 basic medicine ,medicine.medical_specialty ,business.industry ,Immunology ,Induction chemotherapy ,Myeloid leukemia ,Cell Biology ,Hematology ,Biochemistry ,Gastroenterology ,Chemotherapy regimen ,Dasatinib ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Imatinib mesylate ,Nilotinib ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Cytarabine ,Acute Myeloid Leukemia with BCR-ABL1 ,business ,medicine.drug - Abstract
Various chemotherapy regimens attempted however have been evaluated these treatment e not effective in chronic myeloid leukemia myeloid blastic phase (CML-MBP). Imatinib treatment in this subset of patients were also not very promising due to low response rates, short response duration, and transformation to BC. Some studies showed that nilotinib or dasatinib were superior to imatinib in terms of rapid time to response?? and higher molecular response in newly diagnosed CML patients . It can be translated to CML-MBP. We evaluated 2nd generation TKI, nilotinib and high-dose daunorubicin induction chemotherapy combination if to attempt an improvement in the response rate and survival in patients with CML-MBP or acute myeloid leukemia with BCR/ABL1 (AML-BCR/ABL1). The primary end point of the study was complete remission (CR) rate after induction chemotherapy (IC). Patients received cytarabine 200 mg/m2/day by continuous IV infusion over 24 hours daily for 7 days (D 1-7) along with daunorubicin 90 mg/m2/day IV daily for 3 days (D 1-3). Nilotinib 400mg bid PO was added without interruption from D8 of induction chemotherapy until allogeneic hematopoietic cell transplantation (alloHCT) or during 2 years. Re-induction chemotherapy was given as cytarabine 200 mg/m2/day by continuous iv infusion over 24 hours daily for 5 days (D 1-5) plus daunorubicin 45 mg/m2/day iv daily for 2 days (D 1-2) when D14 bone marrow blasts exceeded 5%. Four courses of high-dose cytarabine (Cytarabine 3 g/m2) were administered in 3-hour IV infusion every 12 hours on days 1, 3, and 5 (a total of six doses per course). This prospective phase II study was early terminated due to slow enrollment. A total of 10 (6 male & 4 female) patients were enrolled. Six patients were diagnosed as CML-MBP and 4 patients as AML-BCR/ABL1 (all these patients will be presented as CML-MBP). Median age CML-MBP patients was 50.9 (22.5-63.0) years. Five patients had received prior therapies (low-dose cytarabine in 1, imatinib in 2 and dasatinib in 2 patients). Median time from CML-MBP diagnosis to induction chemotherapy was 3.12 (0-3.12) months. All patients received IC. Nilotinib was interrupted temporarily during IC in 5 patients (hyperbilirubin emia in 2 pts?, cytopenia in 1, rash in 1 and poor general condition in 1 patient). Nine patients showed bone marrow (BM) blast In conclusion, nilotinib combined with IC is feasible and can be a good bridging therapy for these extremely rare CML-MBP or AML-BCR/ABL1 if they are IC-eligible although this conclusion is very limited and should be confirmed by large scale studies because of the small sample size of this study. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
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- 2018
14. Androgen Therapy for Lower-Risk Myelodysplastic Syndrome
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Miee Seol, Eun-Ji Choi, Young-Shin Lee, Jung-Hee Lee, Han-Seung Park, Ji Min Woo, Kyoo Hyung Lee, Je-Hwan Lee, Mijin Jeon, and Young-Ah Kang
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Danazol ,medicine.medical_specialty ,Cytopenia ,Univariate analysis ,business.industry ,Immunology ,Hazard ratio ,Cell Biology ,Hematology ,Lower risk ,medicine.disease ,Biochemistry ,Gastroenterology ,International Prognostic Scoring System ,Androgen Therapy ,Internal medicine ,Oxymetholone ,medicine ,business ,medicine.drug - Abstract
Background Improvement of cytopenia is one of the primary treatment purposes for patients with the lower-risk myelodysplastic syndrome (MDS). Androgens have been used for the treatment of aplastic anemia, immune thrombocytopenia, and telomere diseases. In this retrospective study, we aimed to evaluate the efficacy of androgen therapy in lower-risk MDS. Methods We analyzed the data of 139 patients who received androgens (danazol or oxymetholone) for treatment of cytopenia between February 1997 and May 2018. All patients had the international prognostic scoring system low or intermediate-1 risk at the time of androgen therapy. The assessment of hematologic improvement (HI) was based on the international working group response criteria for MDS. Results Androgens (oxymetholone for 83 patients and danazol for 56) were given as first (n=108, 77.7%) or over second (n=31, 22.3%)-line treatment for MDS (Table 1). The time interval between diagnosis and androgen treatment was median 1.3 months (range, 0-240.6), and 75 patients (54.0%) were red blood cell (RBC) transfusion-dependent before treatment. The dose intensity of oxymetholone and danazol was 79 and 385 mg/day respectively, and the median treatment duration was 5.8 months (range, 0.9-92.2). Seventy-nine patients (56.8%) achieved HI at any lineage: 29.0% for erythroid (HI-E), 51.9% for platelet (HI-P), and 60.5% for neutrophil (HI-N). The median time to HI following androgen therapy was 4.1 months (range, 0.6-124.5) for HI-E, 1.7 (range, 0.4-40.4) for HI-P, and 1.8 (range, 0.2-8.4) for HI-N. In univariate analysis, presence of RBC transfusion-dependence (46.7% vs. 68.8%, P=.009), pre-treatment low hemoglobin (45.2% vs. 74.5%, P=.001), high platelet count (46.5% vs. 73.6%, P=.002), and high neutrophil count (4.94% vs. 67.2%, P=.036) were associated with lower HI rate (Table 2). In multivariate analysis, pre-treatment low hemoglobin, high platelet count, and high neutrophil count remained as significant factors for lower HI rate (Table 2). During the median follow-up duration of survivors of 40.8 months (95% confidence interval [CI], 38.0-67.5), the estimated 5-year overall survival (OS) and acute myeloid leukemia-free survival was 68.8% and 67.7%, respectively. Achievement of HI was associated with longer OS (hazard ratio, 0.346; 95% CI, 0.174-0.688). There were no significant differences in HI and OS rates between danazol and oxymetholone. Conclusion Our data suggest that androgen can be a reasonable treatment option for lower-risk MDS patients with significant cytopenia. Prospective studies are warranted to investigate the efficacy of androgen therapy in lower-risk MDS. Disclosures No relevant conflicts of interest to declare.
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- 2018
15. Allogeneic Hematopoietic Cell Transplantation for Severe Idiopathic Aplastic Anemia Older Than 40y
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Hawk Kim, Sung Hwa Bae, Sung-Soo Yoon, Jeong Yeal Ahn, Yeung-Chul Mun, Yunsuk Choi, Young Rok Do, Hyeoung-Joon Kim, Ho Sup Lee, Yong Park, Ji Hyun Lee, Min Kyoung Kim, Sang Kyun Sohn, Soo Mee Bang, Won-Sik Lee, and Kyoo-Hyung Lee
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medicine.medical_specialty ,Neutrophil Engraftment ,Platelet Engraftment ,business.industry ,medicine.medical_treatment ,Immunology ,Bone marrow failure ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Fludarabine ,Transplantation ,Internal medicine ,medicine ,Aplastic anemia ,business ,Survival rate ,medicine.drug - Abstract
Upfront allogeneic hematopoietic cell transplantation (alloHCT) as first line therapy for older than 40 or 50 years is not usually recommended for severe aplastic anemia patients even though there are suitable matched sibling donors because they usually have poor outcomes after alloHCT. Therefore, first line immune suppression therapy (IST) is recommended. However, current outstanding alloHCT outcome can make it possible to try upfront alloHCT even in older AA patients. The purpose of this retrospective study is to determine the transplantation-related results in AA patients older than 40 years. This study collected data retrospectively for older AA patients. Congenital bone marrow failure was excluded from this study. alloHCT was divided as upfront and second alloHCT according to prior IST. Total 129 patients were enrolled in this study from 2001 to 2017. Age at diagnosis and at alloHCT were 25 to 63 (median 48.0) years and 40.3-64.9 (median 49.1) years, respectively. Median time from diagnosis to alloHCT was 5.2 (range, 1-234.1) months. Upfront and second alloHCT were 42 and 87 patients, respectively. Upfront alloHCT received more stem cells from related donors, more BM stem cells and more fludarabine conditioning compared with second alloHCT (83.3% vs. 58.6%, p=0.005; 52.4% vs. 74.7%, p=0.011; 52.4% vs. 30.2%, p=0.015, respectively). However, ABO mismatching (p=0.747), TBI conditioning (p=0.547), cyclophosphamide conditioning (p=0.114), ATG conditioning (p=0.483) were similar between upfront and second alloHCT. Any engraftment failure, neutrophil engraftment failure and platelet engraftment failure were similar between upfront and second alloHCT (28.6% vs. 28.7%, p=0.985; 19.0% vs. 18.4%, p=0.928; 19.0% vs. 34.5%, p=0.072). Hepatic SOS, acute GvHD and chronic GvHD were also similar between upfront and second alloHCT (4.8% vs. 5.7%, p=0.817; 28.6% vs. 36.5%, p=0.376; 19.0% vs. 19.5%, p=0.947). Survival rates at 1Y, 2Y, 3Y and 5Y were 90.7, 82.2, 73.5 and 64.3%, respectively. Survival rates at 5 years in upfront and second alloHCT were 76.2 and 54.1%, respectively (p=0.059). Survival rates at 5 years (5YSR) in age 40-50y, 50-60y, and older than 60y were 64.1, 62.4 and 50.0%, respectively (p=0.349). alloHCT from matched related donor or other donors had similar survival rates (p=0.404). However, upfront alloHCT showed superior survival rate (5YSR 76.5% vs. 53.2%, p=0.114) without statistical significance compared with second alloHCT even in matched related donor subgroup. This trend is similar in alternative donor subgroup (5YSR 75.0% in upfront alloHCT vs. 54.9% in second alloHCT, p=0.459). alloHCT in older AA showed promising results even in patient older than 60 years although upfront alloHCT showed marginal statistical superiority. In conclusion, upfront alloHCT in older AA needs further confirmation by prospective studies. Disclosures No relevant conflicts of interest to declare.
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- 2018
16. OBFC2A/RARA: a novel fusion gene in variant acute promyelocytic leukemia
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Kyoo-Hyung Lee, Eul-Ju Seo, Hyun-Sook Chi, Dahae Won, So Youn Shin, Chan-Jeoung Park, Jin-Ok Lee, and Seongsoo Jang
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Acute promyelocytic leukemia ,Immunology ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Fusion protein ,Molecular biology ,Fusion gene ,Retinoic acid receptor ,Exon ,Promyelocytic leukemia protein ,Tretinoin ,Retinoic acid receptor alpha ,medicine ,biology.protein ,medicine.drug - Abstract
Acute promyelocytic leukemia is characterized by the rearrangement of the retinoic acid receptor α (RARA) gene and its fusion with other genes. We report a novel case of variant acute promyelocytic leukemia with the karyotype der (2)t(2;17)(q32;q21). Array comparative genomic hybridization revealed distinct chromosome breakpoints within the RARA and oligonucleotide/oligosaccharide-binding fold containing 2A (OBFC2A) genes. Sequence analysis of the OBFC2A/RARA transcript showed that exon 5 of OBFC2A was fused with exon 3 of RARA through the same breakpoint as in previously described fusions of RARA. The single-stranded DNA binding protein encoded by OBFC2A is critical for genomic stability. Retention of the OB fold domain of OBFC2A in the fusion protein suggests the possibility of homodimerization. The leukemic cells from the patient showed neutrophilic differentiation in the in vitro all-trans retinoic acid assay. Mutation or rearrangement of the OBFC2A gene has not been previously reported in congenital or acquired disorders.
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- 2013
17. A randomized trial comparing standard versus high-dose daunorubicin induction in patients with acute myeloid leukemia
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Je-Hwan, Lee, Young-Don, Joo, Hawk, Kim, Sung Hwa, Bae, Min Kyoung, Kim, Dae Young, Zang, Jung-Lim, Lee, Gyeong Won, Lee, Jung-Hee, Lee, Jae-Hoo, Park, Dae-Young, Kim, Won-Sik, Lee, Hun Mo, Ryoo, Myung Soo, Hyun, Hyo Jung, Kim, Young Joo, Min, Yae-Eun, Jang, and Kyoo-Hyung, Lee
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Adult ,Male ,medicine.medical_specialty ,Myeloid ,Adolescent ,Daunorubicin ,Immunology ,Biochemistry ,Gastroenterology ,Disease-Free Survival ,Young Adult ,Internal medicine ,medicine ,Humans ,Antibiotics, Antineoplastic ,business.industry ,Remission Induction ,Hazard ratio ,Myeloid leukemia ,Induction chemotherapy ,Cell Biology ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Surgery ,Leukemia, Myeloid, Acute ,Leukemia ,Treatment Outcome ,medicine.anatomical_structure ,Toxicity ,Cytarabine ,Female ,business ,Follow-Up Studies ,medicine.drug - Abstract
We conducted a phase 3 randomized trial comparing 2 different doses of daunorubicin as induction chemotherapy in young adults (60 years of age or younger) with acute myeloid leukemia (AML). Of 383 patients who were analyzed, 189 received standard-dose daunorubicin (SD-DN, 45 mg/m2 per day times 3 days) and 194 received high-dose daunorubicin (HD-DN, 90 mg/m2 per day times 3 days) in addition to cytarabine (200 mg/m2 per day times 7 days) to induce complete remission (CR). The CR rates were 72.0% in the SD-DN arm and 82.5% in the HD-DN arm (P = .014). At a median follow-up of 52.6 months, overall (OS) and event-free (EFS) survival were higher in the HD-DN arm than in the SD-DN arm (OS, 46.8% vs 34.6%, P = .030; EFS, 40.8% vs 28.4%, P = .030). Differences in CR rate and both OS and EFS remained significant after adjusting for other variables (CR, hazard ratio [HR], 1.802, P = .024; OS, HR, 0.739, P = .032; EFS, HR, 0.774, P = .048). The survival benefits of HD-DN therapy were evident principally in patients with intermediate-risk cytogenetic features. The toxicity profiles were similar in the 2 arms. In conclusion, HD-DN improved both the CR rate and survival duration compared with SD-DN in young adults with AML. This study is registered at www.clinicaltrials.gov as #NCT00474006.
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- 2011
18. Role of Daunorubicin Dose Intensification for Induction Therapy in Acute Myeloid Leukemia Patients with FLT3-ITD Mutants
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Jung-Hee Lee, Eun-Ji Choi, Han-Seung Park, Ji Min Woo, Kyoo-Hyung Lee, Sun-Hye Ko, Je-Hwan Lee, and Miee Seol
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Acute promyelocytic leukemia ,Daunorubicin ,business.industry ,Immunology ,Mutant ,Myeloid leukemia ,Cell Biology ,Hematology ,Impedance threshold device ,medicine.disease ,Biochemistry ,Induction therapy ,medicine ,Cancer research ,Idarubicin ,Dose intensification ,business ,medicine.drug - Abstract
Background Patients with FLT3-ITD mutated acute myeloid leukemia (AML) have generally poor survival. Recent update of ECOG trial comparing standard- vs. high-dose daunorubicin showed that daunorubicin dose intensification improved survival in AML with FLT3-ITD mutants (Blood 2016;127:1551). In subgroup analysis of our previous randomized trial, high-dose daunorubicin seemed to be more effective than idarubicin in AML patients with FLT3-ITD mutants (ASH abstract No. 2535, 2015). In this retrospective investigation, we aimed to evaluate the role of daunorubicin dose intensification for induction therapy in AML patients with FLT3-ITD mutants who were treated at a single institute. Methods We analyzed data from 120 patients of newly diagnosed FLT3-ITD mutated AML patients who received induction chemotherapy between January 2002 and March 2016. The regimens consisted of high-dose daunorubicin (HD-DN, 90 mg/m2/d x 3d, n=39), standard-dose daunorubicin (SD-DN, 45 mg/m2/d x 3d, n=48), or idarubicin (IDA, 12 mg/m2/d x 3d, n=33) in combination with cytarabine (200 mg/m2/d x 7d). Patients with acute promyelocytic leukemia were not included. Results After the first round of induction chemotherapy, 53 patients had persistent leukemia; 50 received the second round of induction chemotherapy consisting of daunorubicin (45 mg/m2/d x 2d) or idarubicin (8 mg/ m2/d x 2d) in addition to cytarabine (200 mg/m2/d x 5d) and 3 received other regimens. A total of 81 patients achieved CR, and the CR rates were 76.9%, 58.3%, and 69.7% in HD-DN, SD-DN, and IDA, respectively (P=0.175). The 4-year cumulative incidence of relapse (CIR) of these 81 patients was 48.8%. With the median follow-up duration of survivors of 59.9 months (range, 4.6-170.7), 4-year overall survival (OS) and event-free survival (EFS) were 57.1%/27.7%/35.7% (P=0.025) and 45.2%/23.9%/36.0% (P=0.042) in HD-DN, SD-DN, and IDA, respectively. HD-DN showed statistically higher OS (hazard ration [HR], 0.424; P=0.005) and EFS (HR, 0.497; P=0.01), and lower CIR (P=0.036) than SD-DN, while OS and EFS differences between HD-DN and IDA were not statistically significant. Conclusion Daunorubicin dose intensification for induction therapy seemed to be effective in AML patients with FLT3-ITD mutants. Further studies are needed to investigate whether HD-DN is superior to IDA in this population. Considering high relapse rate, combination strategies of daunorubicin dose intensification and targeted agents such as FLT3 inhibitors should be developed. Disclosures No relevant conflicts of interest to declare.
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- 2016
19. Allogeneic Hematopoietic Cell Transplantation for Lymphoma: Baseline and Post-Transplant Prognostic Factors
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Kyoo-Hyung Lee, Je-Hwan Lee, Sun-Hye Ko, Han-Seung Park, Eun-Ji Choi, Jung-Hee Lee, Young-Ah Kang, and Young-Shin Lee
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Oncology ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Retrospective cohort study ,Cell Biology ,Hematology ,Disease ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Chemotherapy regimen ,Lymphoma ,Transplantation ,surgical procedures, operative ,International Prognostic Index ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Adverse effect ,business - Abstract
Background: Allogeneic hematopoietic cell transplantation (HCT) has been increasingly used for the treatment of lymphoma. The outcomes of HCT in lymphoma depend on baseline patient characteristics including chemosensitivity and International Prognostic Index (IPI). Several studies have shown that post-transplant occurrence of acute or chronic graft-versus-host disease (GVHD) and immune recovery might be associated with the outcomes. In this retrospective study, we investigated baseline and post-transplant prognostic factors in lymphoma patients receiving allogeneic HCT. Patients and methods: Between May 1998 and December 2015, a total of 61 patients underwent allogeneic HCT for lymphoma and the median age was 39 years (range, 16-62 years). Thirty four patients (55.7%) had chemo-sensitive disease and 24 patients had received autologous HCT. Fifty-six of 61 patients received reduced-intensity conditioning regimens. We evaluated tumor response, overall survival (OS), progression-free survival (PFS), non-relapse mortality (NRM), and event-free survival (EFS) after allogeneic HCT along with potential prognostic factors including GVHD and immune reconstitution. Results: Objective tumor response after HCT was observed in 41 (67.2%; complete 30 and partial 11). The 5-year probabilities of OS, NRM, PFS, and EFS were 30.7%, 23.5%, 41.3%, and 24.0%, respectively. Among the baseline characteristics, chemosensitivity had a significant impact on OS, NRM, and EFS. Persistent disease status at allogeneic HCT had an adverse effect on OS and low IPI risk category at HCT was associated with longer OS and EFS. HCT co-morbidity index ≥1 was an independent prognostic factor for higher NRM. Grade III-IV acute GVHD was associated with lower OS and higher NRM. Severe chronic GVHD had higher OS (60.0% vs. 19.8%, P=0.002), PFS (68.8% vs.35.9%, P Conclusion: Chemosensitivity was the most important prognostic factor in allogeneic HCT for lymphoma. Acute GVHD had unfavorable impact, whereas, chronic GVHD had favorable impact on post allogeneic HCT outcomes. Early immune recovery could predict allogeneic HCT outcomes. Disclosures No relevant conflicts of interest to declare.
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- 2016
20. Expression of JL1 Antigen in Acute Leukemia and Myelodysplastic Syndrome
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Jung-Hee Lee, Eun-Ji Choi, Han-Seung Park, Dae-Young Kim, Kyoo-Hyung Lee, Soseul Kim, Je-Hwan Lee, Kyeongcheon Jung, Chan-Jeoung Park, Sangsoon Yoon, and Eun-Hye Hur
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Oncology ,medicine.medical_specialty ,NPM1 ,Acute leukemia ,business.industry ,Immunology ,CD34 ,Myeloid leukemia ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Leukemia ,Antigen ,hemic and lymphatic diseases ,Internal medicine ,Acute lymphocytic leukemia ,medicine ,Cytarabine ,business ,medicine.drug - Abstract
Background: The JL1 antigen is a novel epitope of CD43, a cell surface glycoprotein of mucin family. JL1 is a differentiation antigen expressed on stage II double positive (CD4+CD8+) human cortical thymocytes. The antigen is not expressed on mature peripheral blood cells or other normal tissues. The anti-JL1 monoclonal antibody binds to human leukemia MOLT-4 cells with 5,100-9,600 binding sites per cell. Preclinical studies have shown the cytotoxic effects of anti-JL1-based immunotoxin against JL1-positive leukemic cells, sparing most normal tissues other than thymocytes and some bone marrow mononuclear cells. Phase I clinical trial of new anti-leukemic agent with an anti-JL1 antibody (Leukotuximab; DiNonA, Korea) is now underway. In this study, we prospectively investigated the JL1 expression in patients with acute leukemia and myelodysplastic syndrome (MDS). Patients & methods: Flow cytometric analysis for the JL1 expression on leukemic blasts was performed using a FACSCanto II (Becton-Dickinson, Sunnyvale, CA, USA). The percent expression of JL1 antigen among leukemic blasts was recorded. Positive JL1 expression was defined if 20% or more leukemic blasts expressed the antigen. Association of JL1 expression with clinical, pathologic, and genetic characteristics was analyzed. Influence of JL1 expression on clinical outcomes of patients was also explored. Results: Between March 2014 and June 2015, a total of 245 adult patients with acute myeloid leukemia (AML, n=170), acute lymphoblastic leukemia (ALL, n=52), and MDS (n=23) were enrolled in this study. Positive JL1 expression was observed in 96 (57.1%) patients with AML, 28 (51.9%) with ALL, and 5 (21.7%) with MDS (P =0.006), while three normal controls showed negative JL1 antigen expression. Interestingly, JL1 expression was positive in all 14 patients with AML M3 with a median expression of 94.3% (range, 60.3-97.8%). In contrast, only 13 (39.4%) of 33 patients with AML with myelodysplasia-related changes (MRC) had positive JL1 expression. In AML patients, positive JL1 expression was significantly associated with CD34- (P =0.003), HLA-DR- (P =0.019), PML-RARA + (P =0.001), FLT3-ITD + (P =0.026), mutated NPM1 (P =0.003), and complex karyotype (3 or more clonal chromosomal abnormalities) (P =0.020). Cytarabine plus anthracycline based chemotherapy was given to 117 patients with AML, and the complete remission (CR) rate was significantly different between 63 JL1 expression positive patients and 54 negative patients (84.1% vs. 59.3%, P =0.003). Positivity of JL1 expression was not significantly associated with overall survival in all patients with AML (median survival, JL1 positive vs. negative, 20.6 vs. 18.2 months, P =0.489). In ALL patients, positive JL1 expression was significantly associated with CD13- (P =0.032) and the CR rate was not significantly different by JL1 expression. JL1 expression was measured twice or more in 85 patients during their clinical courses and positivity of JL1 expression was not changed in 61 (71.8%) (P =0.307). Five MDS patients progressed to AML and JL1 expression was changed in only one patient (JL1 positive to JL1 negative). Conclusion: JL1 was expressed in around 50% of patients with AML or ALL while less frequent expression of JL1 was observed in MDS and AML with MRC. JL1 expression was significantly associated with some immunophenotypic and genetic features, especially PML-RARA +. JL1 expression was significantly associated with the CR rate of AML patients. Expression of JL1 seems to be stable during clinical courses. Our data suggest that immunotherapeutic approach targeting JL1 antigen may be feasible in significant proportion of patients with acute leukemia and MDS. Disclosures Kim: Dinona Institute, Dinona Inc.: Employment. Yoon:Dinona Institute, Dinona Inc.: Employment. Jung:Dinona Institute, Dinona Inc.: Employment.
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- 2015
21. Frequency, Characteristics and Prognostic Significance of RUNX1 mutations in Patients with Acute Myeloid Leukemia, Not Otherwise Specified
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Mi Hyun Bae, Dae-Young Kim, Seongsoo Jang, Young-Uk Cho, Yoon Hwan Chang, Je-Hwan Lee, Kyoo-Hyung Lee, Eul-Ju Seo, In-Suk Kim, Jung-Hee Lee, Bohyun Kim, Chan-Jeoung Park, and Donghyun Lee
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Oncology ,medicine.medical_specialty ,NPM1 ,Immunology ,Nonsense mutation ,Not Otherwise Specified ,Myeloid leukemia ,Cell Biology ,Hematology ,Biology ,Trisomy 8 ,medicine.disease ,Bioinformatics ,Biochemistry ,hemic and lymphatic diseases ,Internal medicine ,CEBPA ,medicine ,Trisomy ,Patau's syndrome - Abstract
Background: Somatic mutations in RUNX1 gene have been identified in a substantial proportion of patients with de novo acute myeloid leukemia (AML). It is suggested as a new candidate molecular marker and, therefore, is suggested to be routinely performed at the diagnostic stage of AML. Despite its clinical importance, however, previous cohorts have been heterogeneous in terms of cytogenetic and molecular subtypes of AML. Here, the aim of this study was to evaluate the frequency, biologic characteristics, and prognostic significance of RUNX1 mutations focusing on patients with AML, not otherwise specified (NOS). Methods: Diagnostic samples from 202 patients with AML were analyzed for RUNX1 mutations. We excluded AML with recurrent genetic abnormalities, AML with myelodysplasia-related changes, and therapy-related AML because these entities have prognostic relevances of their own. RUNX1 mutations were detected using standard PCR techniques and direct sequencing. Results: RUNX1 mutations were found in 27 (13.4%) patients. The mutations were clustered in Runt homology domain (13, 48.1%) and transactivation domain (9, 33.3%). Frameshift mutations were most common (52.9%), followed by missense mutations (35.3%) and nonsense mutations (11.8%). As shown in Table 1, patients with RUNX1 mutations had a lower platelet count (P = 0.03), a higher rate of trisomy 8 (P = 0.02) and trisomy 13 (P = 0.039), and a trend toward older age (P = 0.063) than patients without mutations. Presence of RUNX1 mutations and NPM1 or CEBPA mutations were mutually exclusive. At the median follow-up of 12.1 months, RUNX1 mutations predicted for shorter overall survival (OS; P = 0.007) and relapse-free survival (RFS; P = 0.003). In the multivariate analysis, RUNX1 mutation was a significant marker for inferior OS (hazard ratio, 3.037; P = 0.014) and RFS (hazard ratio, 5.699; P = 0.001). Conclusion: The findings of our study further strengthen the previous data about RUNX1 mutations in AML. Furthermore, AML NOS with RUNX1 mutations is characterized by distinct biology and is associated with adverse clinical outcome. Our study supports the notion that RUNX1 mutational status would be integrated into diagnostic workup of AML, particularly for AML, NOS subgroup. Table 1. Clinical and biologic features of the cohort by RUNX1 mutations RUNX1 mutations P -value Mutated, n (%) Wild type, n (%) Number 27 (13.4) 175 (86.6) Male sex 17 (63.0) 94 (53.7) 0.489 Median age, years (range) 63 (14 - 80) 55 (1 - 83) 0.063 WBC count, ¡¿109/L (median, range) 7.9 (1.1 - 133.3) 14.0 (0.8 - 231.3) 0.636 Hemoglobin, g/dL (median, range) 8.6 (5.0 - 10.6) 8.8 (4.1 - 17.3) 0.376 Platelet count, ¡¿109/L (median, range) 35 (14 - 230) 59 (9 - 900) 0.03 Blood blasts, % (median, range) 29 (0 - 94) 38.5 (0 - 93) 0.312 FAB subtypes M0 3 (11.1) 11 (6.3) 0.609 M1, M2 21 (77.8) 129 (73.7) 0.831 M4, M5 3 (11.1) 27 (15.4) 0.767 M6, M7 0 8 (4.6) 0.546 Cytogenetic abnormalities Normal karyotype (%) 11 (40.7) 104 (59.4) 0.106 Trisomy 8 (%) 5 (18.5) 8 (4.6) 0.02 Trisomy 11 (%) 1 (3.7) 4 (2.3) 0.823 Trisomy 13 (%) 3 (11.1) 3 (1.7) 0.039 Trisomy 21 (%) 1 (3.7) 2 (1.1) 0.866 Distribution of other mutations FLT3 -ITD 5 (18.5) 50 (28.6) 0.39 FLT3 -TKD 1 (3.7) 4 (2.3) 0.823 NPM1 0 55 (31.4) 0.002 CEBPA 0 17 (9.7) 0.187 MLL -PTD 1 (3.7) 14 (8.0) 0.691 Disclosures No relevant conflicts of interest to declare.
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- 2015
22. A Prospective Randomized Comparison of Idarubicin and High-Dose Daunorubicin in the Induction Chemotherapy for Acute Myeloid Leukemia
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Myung Soo Hyun, Hawk Kim, Sung Hwa Bae, Min Kyoung Kim, Yunsuk Choi, Won Sik Lee, Jung Lim Lee, Young-Don Joo, Jihyun Kwon, Jung-Hee Lee, Sang Min Lee, Hun-Mo Ryoo, Kyoo-Hyung Lee, Gyeong Won Lee, Sung-Nam Lim, Je-Hwan Lee, Dae Young Zang, Hyo Jung Kim, and Dae-Young Kim
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Acute promyelocytic leukemia ,medicine.medical_specialty ,business.industry ,Daunorubicin ,Immunology ,Induction chemotherapy ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Chemotherapy regimen ,Transplantation ,Internal medicine ,medicine ,Cytarabine ,Idarubicin ,business ,Etoposide ,medicine.drug - Abstract
Introduction: We conducted a randomized trial comparing two different doses of daunorubicin as induction chemotherapy in young adults with acute myeloid leukemia (AML) and showed intensification of induction therapy using a high daily dose of daunorubicin (90 mg/m2/d x 3d) improved both complete remission (CR) rate and survival duration compared to standard daunorubicin dose (45 mg/m2/d x 3d) (Lee JH et al. Blood 2011;118:3832). As it is necessary to compare the effects of high-dose daunorubicin with that of other agents, especially idarubicin, we performed another randomized trial comparing two induction regimens in young adults with AML: idarubicin vs. high-dose daunorubicin (ClinicalTrials.gov #NCT01145846). Here, we present final results of the study. Methods: Between May 2010 and March 2014, a total of 316 patients (65 years or younger) with newly diagnosed AML except acute promyelocytic leukemia were registered in this study. Seventeen patients were removed from the study (change of diagnosis in 11, patient's refusal to be randomized in 3 and other in 3) and the remaining 299 patients were analyzed. After random assignments, 149 patients received idarubicin (AI, 12 mg/m2/d x 3d) and 150 patients received high-dose daunorubicin (AD, 90 mg/m2/d x 3d) in addition to cytarabine (200 mg/m2/d x 7d) for induction of CR. Patients with persistent leukemia received the second attempt of induction chemotherapy, consisting of idarubicin (AI, 12 mg/m2/d x 2d) or daunorubicin (AD, 45 mg/m2/d x 2d) plus cytarabine (5d). Patients who attained CR received 4 cycles of high-dose cytarabine (3 g/m2 x 6 doses) in patients with good- or intermediate-risk cytogenetics and 4 cycles of cytarabine (1 g/m2 x 6d) plus etoposide (150 mg/m2 x 3d) in those with high-risk cytogenetics. Hematopoietic cell transplantation (HCT) was performed according to attending physician's discretion after one or two cycles of consolidation chemotherapy in most transplant cases. Results: CR was induced in 232 (77.6%) of 299 patients. Reasons for induction failure were resistant disease in 50, hypoplastic death in 5, and indeterminate cause in 12. As postremission therapy, 3 patients received no further treatment, 71 received consolidation chemotherapy without HCT, 137 underwent allogeneic HCT, and 21 underwent autologous HCT. The CR rates were not significantly different between two arms: 80.5% (120 of 149, AI) vs. 74.7% (112 of 150, AD) (P=0.224). With a median follow-up of 1046 days, overall survival probabilities at 4 years were 51.1% in AI vs. 54.7% in AD (P=0.756). The probabilities at 4 years for relapse-free survival were 63.5% in AI vs. 74.2% in AD (P=0.181) and those for event-free survival were 44.8% in AI vs. 50.7% in AD (P=0.738). Toxicity profiles were similar between two arms. Interestingly, overall and event-free survivals of 44 patients with FLT-ITD mutants (27 in AI and 17 in AD) were significantly different according to the induction regimens (AI vs AD; overall survival, 30.8% vs. 61.9%, P=0.030; event-free survival, 31.4% vs. 61.9%, P=0.025). Conclusions: The results of this phase 3 trial, which compared idarubicin (12 mg/m2/d x 3d) with high-dose daunorubicin (90 mg/m2/d x 3d), did not show significant differences between two arms in the outcomes of patients in terms of CR rates and overall, relapse-free or event-free survivals. In subset analysis, high-dose daunorubicin seems to be more effective than idarubicin in patients with FLT-ITD mutants. Disclosures Kim: Celgene: Research Funding; Alexion Pharmaceuticals: Research Funding; Il-Yang: Research Funding; Novartis: Research Funding.
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- 2015
23. Identification of Novel Fusion Genes and Differentially Expressed Genes in Acute Leukemia through Transcriptome Analysis
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Dae-Young Kim, Seongsoo Jang, Mi Hyun Bae, Jung-Hee Lee, Eul-Ju Seo, Kyoo-Hyung Lee, Chan-Jeoung Park, Young-Uk Cho, Donghyun Lee, Jong Jin Seo, and Je-Hwan Lee
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Genetics ,ABL ,Immunology ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Fusion protein ,Molecular biology ,Fusion gene ,Gene expression profiling ,Exon ,Fusion transcript ,Chimeric RNA ,Gene - Abstract
Background Chromosomal translocations in acute leukemia frequently result in gene fusions that are associated with leukemogenesis. Next-generation sequencing technology has opened up a systematic characterization of transcriptomes including gene expression, novel transcript, and fusion transcripts. We used next-generation RNA sequencing to identify fusion genes responsible for novel chromosomal translocations in acute leukemia and to find their differentially expressed genes. Methods We selected 10 acute leukemia (AML, 6; B-ALL, 3; and T-ALL, 1) patients with novel translocations by G-banding. Total RNA was extracted from leukemia cells and cDNA libraries were constructed with TruSeq RNA kit. Paired-end sequencing was performed on HiSeq2500. Reads were aligned with TopHat/BowTie, and deFuse was used to detect fusion transcripts. Transcript assembly and abundance estimation were done using Cufflinks, and expression levels were quantified by fragments per kilobase of transcript per million mapped reads (FPKM). The candidate fusion transcripts were validated with fluorescence in situ hybridization (FISH), and reverse-transcription PCR followed by Sanger-sequencing. Results We found 5 in-frame fusion genes exactly matched on translocation breakpoints from 3 AML patients and 1 B-ALL patient: USP34-ASAP3/t(1;2)(p36.1;p11.2), MAZ-MKL1/t(16;22)(p11.2;q13), MLL-SEPT6 and SEPT6-CDCA5/t(X;11)(q24;q13), and RCSD1-ABL1/t(1;9)(q24;q34). The USP34-ASAP3 fusion produced a novel transcript between USP34 exon 2 and ASAP3 exon 18. The protein encoded by the ASAP3 gene promotes cell differentiation and migration and has been implicated in cancer cell invasion. Comparing gene expression in this sample to nine other samples, we found six overexpressed genes; CLEC3B, SNAR-A14, H19, HOTS, SNORD35A, and S100A1. CLEC3B is associated with human disorders affecting bone and connective tissue. H19 is located in an imprinted region of chromosome 11 and is associated with Wilms tumorigenesis. S100A1 is involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. The MAZ-MKL1 fusion transcript was composed of MAZ exon 4 and MKL1 exon 4. MAZ was a novel partner gene of MKL1 which had been reported in acute megakaryoblastic leukemia carrying RBM15-MKL1/t(1;22)(p13;q13). MS4A2, RPLP0, and ARP5J2 genes were overexpressed in this rearrangement. MS4A2 is related PI3K cascade pathway and immune response pathway. RPLP0 is responsible for RNA binding and structural constituent of ribosome. AML patient with t(X;11)(q24;q13) had two fusion transcripts, MLL-SEPT6 and SEPT6-CDCA5 resulting from complex MLL rearrangement. While the MLL-SEPT6 fusion has been known in AML cases, the SEPT6-CDCA5 was a novel fusion. SNORD88B, MYL6, PTMA, MKX, NDUFAF3, and CNTN1 gene were more highly expressed than other samples. Among them, MKX and CNTN1 genes are related with cell adhesion function. The RCSD1-ABL1/t(1;9)(q24;q34) in B-ALL was previously reported to encode an aberrant tyrosine kinase. This translocation had also reciprocal ABL1-RCSD1 fusion transcript which could result in an alteration of cellular function. Six genes were specifically overexpressed in this sample RCBTB2, SERHL2, MIR941-2, FAM150B, GPR110, and SNORA27. RCBTB2 encodes a protein that is related to regulator of chromosome condensation. We also investigated leukemia subtype-specific expression profiles. The five significant genes were higher expressed in AML as compared with ALL (MIR4461, SET, RNU6ATAC, NINJ2, and ATP6V0C). Especially, MIR4461 was over 6000 FPKM in 5 of 6 AML samples, but was never expressed in ALL samples. B-ALL specific overexpressed genes were C17orf62, and MIR941-1, whereas T-ALL specific overexpressed gene was SNORD33. Conclusions Using next-generation RNA sequencing, we have discovered 5 candidate fusion genes in 10 acute leukemia patients with novel translocations, and identified 3 novel fusion genes to be predicted as oncogenic potential. Through the comparison of expression profiling, we were able to define differentially expressed genes in acute leukemia with novel fusion genes and leukemia subtype-specific gene expression. RNA-sequencing is a powerful tool for the discovery of leukemia-associated fusion genes and their related genes as well as molecular pathways. Disclosures No relevant conflicts of interest to declare.
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- 2015
24. Allogeneic Hematopoietic Cell Transplantation for Acute Myelogenous Leukemia in Remission - a Prospective Comparison of Three Different Donor Groups; Matched Sibling, Matched Unrelated, and Haploidentical Family Donors
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Yoon-Sook Choi, Jae-Cheol Jo, Han-Seung Park, Seunghyun Baek, Je-Hwan Lee, Mijin Jeon, Kyoo-Hyung Lee, Dae-Young Kim, Eun-Ji Choi, Young-Ah Kang, Sung Nam Lim, Miee Seol, Young Shin Lee, Jae Hoo Park, Young-Don Joo, Jung-Hee Lee, and Hawk Kim
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medicine.medical_specialty ,Neutrophil Engraftment ,business.industry ,medicine.medical_treatment ,Immunology ,Hazard ratio ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Gastroenterology ,Surgery ,Transplantation ,Leukemia ,Graft-versus-host disease ,Internal medicine ,medicine ,Prospective cohort study ,business ,Busulfan ,medicine.drug - Abstract
Allogeneic hematopoietic cell transplantation (HCT) from HLA-matched sibling (MS) or unrelated donors (MU) is a well-established treatment for patients with intermediate/high-risk acute myelogenous leukemia (AML) in remission. When HLA-matched donors are not available, however, use of haploidentical family (HF) donors for HCT remains controversial. Therefore, we performed a prospective study, where patients with AML in complete remission (CR) underwent allogeneic HCT according to the donor priority of MS, MU, or HF donors. Conditioning regimen for MS-HCT was busulfan (3.2 mg/kg • 4 days)-cyclophosphamide (60 mg/kg • 2 days) or, for patients >55 years or with co-morbidity, busulfan (3.2 mg/kg • 2 days)-fludarabine (30 mg/m2 • 6 days)-Thymoglobulin (1.5 mg/kg • 3 days). Patients undergoing MU- or HF-HCT received busulfan (3.2 mg/kg • 2 days)-fludarabine (30 mg/m2 • 6 days)-Thymoglobulin (3 mg/kg • 3 days) (Lee K-H et al; Blood 2011;118:2609-2617; Am J Hematol 2011;86:399-405). Ex-vivo T cell depletion was not performed. GVHD prophylaxis included cyclosporine plus a short course of methotrexate. Between January 2010 and December 2014, 244 patients enrolled. Of those, 16 patients were excluded from the analysis (12 patients relapsed before HCT; 3 with major protocol violation; and 1 with incomplete data). Of remaining 228 patients, 81 underwent HCT from MS donors, 90 from MU donors, and 57 from HF donors. The donors for MU-HCT were younger and more male-dominant than those for MS- or HF-HCT. The characteristics of patients and their donors were summarized in Table 1. Table 1. MS-HCT (n=81) UD-HCT (n=90) HF-HCT (n=57) P* Median age, yr (range) 48 (19-66) 43 (16-66) 46 (17-69) Sex, male/female 37/44 44/46 29/28 0.824 CR1/CR2 76/5 82/8 47/10 0.098 Chromosome risk,low**/intermediate/high/high-monosomal 6/57/10/5 4/65/16/3 2/40/7/5 0.751 Donor median age, yr (range) 45 (18-63) 28 (20-45) 29 (15-58) Donor age, yrup to 2526-45over 45 44136 29610 19326 0.000 Donor sex, male/female 46/35 76/14 36/21 0.000 Donor relation, parents/sibling/offspring 7/24/26 HLA allele mismatch/8 (GVH direction), 0/1/2/3/4 81/0/0/0 51/26/10/2/1 0/0/5/22/30 0.000 Graft, bone marrow/peripheral blood 28/53 0/90 0/57 0.000 Median nucleated cell count, •108/kg (range) 8.0 (0.9-19.0) 10.8 (4.1-31.4) 10.8 (5.1-19.3) Median CD34+ count, •106/kg (range) 4.9 (0.8-18.0) 8.0 (1.4-26.2) 6.4 (2.4-25.7) *by Chi-square test; **Twelve patients with AML of low-risk chromosomal abnormality included 6 patients in CR2, 3 with c-kit mutation, and 3 with persistent aml1-eto or cbf beta-myh11 after induction chemotherapy. The median follow-up duration of 164 survivors in the study was 34.7 months (range, 3.7-63.6) after HCT. The donor-group effect on the HCT outcomes was described in Table 2. Patients who underwent MS-HCT showed slightly slower neutrophil engraftment and higher incidence of chronic GVHD. Otherwise, in terms of disease recurrence, NRM, graft failure, EFS, and OS, there was no significant difference according to the donor-type. For AML recurrence, cytogenetic risk was an independent prognostic factors (P =0.003; hazard ratio of low-risk to; intermediate-risk, 1.42; high-risk, 2.53; high-risk with monosomal karyotype, 5.47). Table 1. MS-HCT (n=81) UD-HCT (n=90) HF-HCT (n=57) P Cumulative incidence ( 95% confidence interval)* AML recurrence 29% (19-40%) 26% (17-36%) 35% (20-51%) 0.785 Non-relapse mortality (NRM) 8% (3-16%) 7% (2%-16%) 11% (4-21%) 0.435 Graft failure 1% (0.1-6%) 6% (2-12%) 5% (1-13%) 0.293 ANC>500/uL median days (range) 100% 13 (9-20) 99%12 (10-45) 98% 12 (6-22) 0.049 Platelet>20,000/uL median days (range) 99% (86-100%) 14 (0-83) 97% (88-99%) 13 (0-77) 96% (83-99%) 14 (0-106) 0.352 Grades 2-4 acute graft-versus-host disease (GVHD) 12% (6-21%) 13% (7-21%) 23% (13-34%) 0.176 Moderate to severe chronic GVHD 39% (28-50%) 22% (13-30%) 23% (13-35%) 0.0452 4-year survival** Event-free (EFS) 63% 69% 54% 0.381 Overall (OS) 62% 74% 64% 0.077 *compared by Gray's method; **compared by log-rank test Our study showed that, despite heterogeneity of baseline donor characteristics (age and sex), conditioning regimen, and graft source (bone marrow vs. peripheral blood), overall post-transplant outcomes were similar among recipients from MS-, MU-, and HF-donors. Therefore, for patients with AML in CR but without an HLA-matched donor available, HCT from a haploidentical family member may be considered. Disclosures No relevant conflicts of interest to declare.
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- 2015
25. Long-Term Follow-up of Continuous Imatinib Plus Combination Chemotherapy in Patients with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
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Hun-Mo Ryoo, Dae-Young Kim, Kyoo-Hyung Lee, Ho-Jin Shin, Sung-Nam Lim, Hyun-Sook Chi, Inho Kim, Ho Young Kim, Sang Min Lee, Jong-Ho Won, Deok-Hwan Yang, Min Kyoung Kim, Je-Hwan Lee, Chul Won Jung, Young-Don Joo, Joon Ho Moon, Seonyang Park, Sang Kyun Sohn, Jae Hoon Lee, Hyeon-Seok Eom, Won Sik Lee, Myung Soo Hyun, Hawk Kim, Sung Hwa Bae, Gyeong-Won Lee, Jung-Hee Lee, and Hyeoung Joon Kim
- Subjects
medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Salvage therapy ,Combination chemotherapy ,Imatinib ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Gastroenterology ,Surgery ,Transplantation ,Leukemia ,Imatinib mesylate ,Internal medicine ,medicine ,Cumulative incidence ,business ,medicine.drug - Abstract
Introduction: The effect of imatinib plus combination chemotherapy were assessed in 87 patients, aged 16-71 years, with newly diagnosed Philadelphia Chromosome-Positive (Ph+) acute lymphoblastic leukemia (ALL). Methods: Imatinib (600 mg/day orally) was administered continuously with combination chemotherapy, starting from eighth day of remission induction treatment, then through 5 courses of consolidation or until allogeneic hematopoietic cell transplantation (HCT). Patients who were not transplanted were maintained on imatinib for 2 years. Molecular response monitoring was performed at the central lab (Asan Medical Center) with quantitative RT-PCR assays for peripheral blood or bone marrow BCR-ABL RNA in serial; at the time of diagnosis, at hematologic complete remission (HCR), and every 3 months thereafter. The molecular response was defined as complete (MCR) if the BCR-ABL/G6PDH ratio was less than 1x10-5. Results: Between October 2005 and February 2009, total 89 patients with newly diagnosed Ph+ALL were enrolled. With median follow-up of 5 years among survivors (range: 2.6-8.9 years) and data were frozen up in July, 2014. Two patients were not assessed, one due to a final diagnosis of CML blastic phase and one for refusal of the protocol treatment 4 months after enrollment. Eighty-two patients (94%) achieved HCR at a median 25 days (range, 14-69 days). Among these 82 HCR patients, 40 experienced recurrence of leukemia and 5-year relapse free survival (RFS) rate was 36.8%. Median time of RFS was 33 months (95% CI 20-46 months). In all, 24 patients died without leukemia progression or recurrence. Causes of treatment related morality were infection (n=5), bleeding (n=2), and HCT related complication (n=17). The 5-year overall survival (OS) rate was 33.4% and the median time of OS was 22.9 months (95% CI, 7.95-37.97 months). In total, 56 patients (68%) underwent allogeneic HCT in first HCR and had received a median 2 courses (range, 0-5 courses) of consolidation prior to HCT. At a median follow-up of 5-years (range, 2.1-8.4 years) after HCT, 23 patients experienced leukemia recurrence (cumulative incidence, 59.1%; 95% CI, 49.7%-68.5%). Of these 23 patients, 17 showed new molecular evidence of disease recurrence before hematologic relapse. Six patients, however, experienced hematologic recurrence without preceding molecular evidence of leukemia recurrence. The 5-year OS rate of patient underwent allogeneic HCT at first HCR was 52.6% and the median time of OS was 72.0 months (95% CI, 17.49-126.50 months). In the patients who completed the five cycles of consolidation, 7 patients were maintained on imatinib. Among these 7 patients, four patients finished 2-year imatinib maintenance. At median follow-up of 4 years (range, 1.9-7.4 years) after maintenance, 6 patients relapsed. The median time of RFS of patient who received maintain therapy was 40.7 months (95% CI, 24.38-57.19 months). One patient with relapse received HCT at second HCR after salvage therapy and two patients died with leukemia recurrence. Cumulative MCR rate was 88.5%, and median time to MCR was 54 days (range, 13-384 days). Median time of MCR duration was 13 months (range, 0.9-60.3 months). MCR achievement within 3months after remission induction was significant predictor of RFS (P=0.004) and OS (P=0.003). Thirty two patients who lost of MCR had significantly inferior RFS (P90% vs. ¡Â90%; was significantly associated with median HCR duration (44 vs. 13 months, P=0.001, Fig. 1), median overall survival (39 vs. 10 months, P80% vs. ¡Â80%; was 57% (95% CI, 43.0-75.5%) and 33% (95% CI, 12.3-55.4%), respectively (P=0.05). Conclusions: The higher imatinib dose intensity is correlated with the better molecular response and the superior overall outcome. The quantitative monitoring of BCR-ABL transcript levels is useful in identifying subgroups of Ph+ALL patients at a high risk of relapse. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.
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- 2014
26. A Prospective Randomized Comparison of Cyclophosphamide Versus Fludarabine in Addition of Antithymocyte Globuline for Allogeneic Hematopoietic Cell Transplantation in Patients with Adult Severe Aplastic Anemia; Interim Analysis
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Je-Hwan Lee, Jinny Park, Jae-Cheol Jo, Yeo-Kyeoung Kim, Dae-Young Kim, Young-Don Joo, Kyoo-Hyung Lee, Chul Won Jung, Hawk Kim, Won-Sik Lee, and Jung-Hee Lee
- Subjects
medicine.medical_specialty ,Hepatic veno-occlusive disease ,Cyclophosphamide ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Interim analysis ,Biochemistry ,Gastroenterology ,Surgery ,Fludarabine ,Transplantation ,Internal medicine ,medicine ,Aplastic anemia ,business ,Survival rate ,Hemorrhagic cystitis ,medicine.drug - Abstract
Our previous study showed that a less toxic regimen comprising reduced cyclophosphamide (Cy), fludarabine and anti-thymocyte globulin (ATG) (Cy-Flu-ATG), was less toxic for allogeneic hematopoietic cell transplantation (alloHCT) compared with standard Cy-ATG in patients with adult severe aplastic anemia (AA). We postulated that replacing Cy with Flu (Flu-ATG) would be more beneficial. Therefore we performed a randomized phase III study to compare the regimen-related toxicities (RRTs) of two different conditioning regimens: Cy-ATG vs. Flu-ATG. We present the interim alaysis. Patients in the Cy-ATG arm received Cy at 200 mg/kg. Those in the Flu-ATG arm received fludarabine (Flu) at 180 mg/m2. A total of 36 patients (21 in the Cy-ATG and 15 in the Flu-ATG) were enrolled. The basic patientsÕ characteristics were similar between both arms except for donor type and HLA-matching. There were more unrelated donor (38.1% vs. 73.3%; p=0.037) and HLA mis-matching (0% vs. 40%; p=0.001) in Flu-ATG arm. All predefined RRTs were similar between Cy-ATG and Flu-ATG (33.3% vs. 33.3%; p=1.000). There was no primary engraftment failure in both arms and only one patients in Cy-ATG died of treatment-related hepatic toxicity before engraftment. Also there were no differences between Cy-ATG and Flu-ATG arms in terms of secondary engraftment failure (20% vs. 20%; p=1.000), hepatic sinusoidal obstruction syndrome (0% vs. 0%; p=1.000), hemorrhagic cystitis (4.8% vs. 0%; p=1.000), pulmonary complications (12.5% vs. 16.7%; p=1.000). The incidence of acute graft-versus-host disease (GvHD) (14.3% vs. 20.0%; p=0.677) and chronic GvHD (11.8% vs. 7.7% ; p=1.000) were also similar. The 3-year survival rate did not differ (77.3% vs. 77.0%; p=0.995; Figure 1). Flu-ATG can be Figure 1 promising in terms of RRT without increasing engraftment failure in Flu-ATG arm when considering more unrelated and HLA-mismaching patients were enrolled. We will continue this phase III trial. Figure 1. promising in terms of RRT without increasing engraftment failure in Flu-ATG arm when considering more unrelated and HLA-mismaching patients were enrolled. We will continue this phase III trial. Disclosures No relevant conflicts of interest to declare.
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- 2014
27. Frequency, Clinical Associations, and Prognostic Significance Of Spliceosome Mutations In Patients With Acute Myeloid Leukemia With Myelodysplasia-Related Changes and Therapy-Related Acute Myeloid Leukemia
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Young Jin Kim, Dae-Young Kim, Hyun-Sook Chi, Eul-Ju Seo, Je-Hwan Lee, Kyung Nam Koh, Jung-Hee Lee, Jong-Keuk Lee, Chan-Jeoung Park, Young-Uk Cho, Ho Joon Im, Young-Mi Park, Jong Jin Seo, Sang Hyuk Park, Kyoo-Hyung Lee, and Seongsoo Jang
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Oncology ,medicine.medical_specialty ,Spliceosome ,Myeloid ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Therapy-Related Acute Myeloid Leukemia ,Biology ,Trisomy 8 ,medicine.disease ,Bioinformatics ,Biochemistry ,medicine.anatomical_structure ,Germline mutation ,Internal medicine ,medicine ,Myeloproliferative neoplasm ,Dominance (genetics) - Abstract
Background Recurrent somatic mutation in RNA splicing machinery genes have been identified in a substantial proportion of patients with myelodysplastic syndrome (MDS). The majority of patients with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) or with therapy-related acute myeloid leukemia (tAML) are associated with multilineage dysplasia. However, the clinical and biologic characteristics of AML-MRC and tAML with spliceosome mutations have not been elucidated. Thus, the objective of this study was to evaluate the frequency, clinical associations, and prognostic significance of spliceosome mutations in patients with AML-MRC and tAML. Methods A total of 224 patients were included in this study, consisting 190 cases of AML-MRC and 34 of tAML. U2AF1, SRSF2, and SF3B1 mutations are the three most frequent genes involved with spliceosome mutations in myeloid malignancies, and these mutations were detected using standard PCR techniques and direct sequencing. Results Spliceosome mutations in U2AF1 (S34 and Q157), SRSF2 (P95), and SF3B1 (primarily K700E) were found in 19 (8.5%), 13 (5.8%), and 7 (3.1%) of the 224 patients, respectively. These mutations were mutually exclusive and 17.4% of the patients had one of these mutations. As shown in Table 1, patients with spliceosome mutations had a higher rate of AML-MRC, a prior history of MDS or MDS/myeloproliferative neoplasm (MPN), and intermediate cytogenetic risk compared to patients without mutations. Only one patient with tAML had a spliceosome mutation. Of the patients with AML-MRC diagnosed based solely on MDS-related cytogenetics, only one patient had the U2AF1 mutation. Within the mutation-positive patients, the U2AF1 mutation was associated with younger age (median 47 vs. 66.5 years for other types; P < 0.001), lower WBC count (median 2.4 vs. 10.75 • 109/L for other types; P < 0.001), and higher rate of trisomy 8 (36.8% vs. 0.0% for other types; P = 0.003). The SRSF2 mutation was associated with normal karyotype (61.5% vs. 23.1% for other types, P = 0.03), and the SF3B1 mutation was associated with the presence of ring sideroblasts (71.4% vs. 18.8% for other types, P = 0.012) and a higher rate of complex karyotype (42.9% vs. 3.1% for other types, P = 0.01). There was a trend of male dominance (76.9%) for SRSF2 mutation and a higher frequency of adverse cytogenetic risk (57.1%) for SF3B1 mutation. At the median follow-up of 7.3 months, 122 (54.5%) deaths and 161 (71.9%) events were documented. Overall survival (P = 0.752) and event-free survival (P = 0.864) were similar among patients with or without one of the three mutations, U2AF1, SRSF2, or SF3B1 mutations. Conclusion U2AF1 was the most frequently mutated spliceosome gene among patients with AML-MRC and tAML. The association of spliceosome mutation with a preceding MDS or MDS/MPN suggests that spliceosome mutation has a unique role in the pathogenesis of progression. Although spliceosome mutations were associated with distinct clinical and biologic features in the cohort presented in this study, none of the features were prognostically relevant. Disclosures: Cho: Asan Institute for Life Sciences: Research Funding. Chi:Asan Institute for Life Sciences: Research Funding. Park:Asan Institute for Life Sciences: Research Funding.
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- 2013
28. Comparable Allogeneic Hematopoietic Cell Transplantation Outcome Of Haplo-Identical Family Donor With Matched Unrelated/Mismatched Family Donor In Adult Aplastic Anemia
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Je-Hwan Lee, Jae-Cheol Jo, Hawk Kim, Jae Hoo Park, Dae-Young Kim, Hun-Mo Ryoo, Kyoo Hyung Lee, Jung-Hee Lee, Sung-Hwa Bae, Young-Don Joo, Sang Kyu Park, and Won Sik Lee
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medicine.medical_specialty ,Neutrophil Engraftment ,Platelet Engraftment ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Total body irradiation ,medicine.disease ,Biochemistry ,Gastroenterology ,Transplantation ,Graft-versus-host disease ,Internal medicine ,medicine ,Aplastic anemia ,business ,Busulfan ,medicine.drug - Abstract
Allogeneic hematopoeitic cell transplantation (alloHCT) is a curative therapy for severe/very severe aplastic anemia (sAA) in adult. alloHCT from haplo-identical family donor (HD) is an alternative approach while alloHCT from matched sibling donor (MSD) is the choice of therapy. Our previous study suggested that alloHCT from matched unrelated donor (MUD) were comparable with MSD when pre-transplantation conditions were well-matched. It means poor outcome of MUD might come from poor pre-transplantation clinical factors such as delayed alloHCT. Same will be applied to HD. In this study we compared HD with alternative donors (AD; MUD or mismatched family donor) by matched case study. We selected AD cases from KSBMT2007-01 study population who had comparable pre-transplantation clinical factors with HD by propensity-score matching. Pre-tranplatation clinical factors such as age, ATG conditioning or ABO-compatibility were matched. Therefore 48 AD cases were selected for the comparison with 16 HD cases. Male (p=0.009) and female to male transplantation (p=0.002) were more frequent in HD. AD received prior immune suppression therapy (IST) frequently (p=0.092). Cyclophosphamide (p500/μL, days°×18 (15.4-20.6)13 (11.2-14.8)0.003Time to platelet>20K/μL, day°×s25 (21.4-28.6)15 (5.7-24.3)0.772CI of aGvHD, days°×-86 (19.4-152.6)0.378CI of grade 3/4 aGvHD, days°×--0.255CI of cGvHD, months°×-10.4 (0-35.3)0.202CI of extensive cGvHD, months°×9.5 (5.1-13.9)7.3 (1.9-12.8)0.918°× Median (95% confidence interval), calculated by Gray's testAbbreviations: SOS, sinusoidal obstruction syndrome; aGvHD, acute graft-versus-host disease; cGvHD, chronic graft-versus-host disease; ANC, absolute neutrophil count, CI, cumulative incidenceFigure 1Overall survivalFigure 1. Overall survival In conclusion, alloHCT from HD in sAA is comparable with alloHCT from AD when pre-transplantation clinical factors were similar although extensive chronic GvHD seemed frequent in HD. Therefore alloHCT from sAA could be alternative approach of alloHCT from MUD in adult sAA. Disclosures: No relevant conflicts of interest to declare.
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- 2013
29. Nilotinib Combined With Multi-Agent Chemotherapy For Adult Patients With Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Final Results Of Prospective Multicenter Phase 2 Study
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Jae Hoon Lee, Hyeon Seok Eom, Je-Jung Lee, Kihyun Kim, Hyun-Sook Chi, Yeung-Chul Mun, Kyoo-Hyung Lee, Jae-Sook Ahn, Inho Kim, Young-Uk Cho, Jinny Park, Hawk Kim, Young Don Joo, Sung-Doo Kim, Won Sik Lee, Seonyang Park, Young Jin Kim, Sung-Soo Yoon, Joon Ho Moon, Gyeong Won Lee, Sang Kyun Sohn, Dong Hwan Kim, Sung-Nam Lim, Jung-Hee Lee, Myoung Soo Hyun, Dae-Young Kim, Yang Soo Kim, Chul Won Jung, Je-Hwan Lee, Jong Ho Won, Deok-Hwan Yang, and Ho-Jin Shin
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medicine.medical_specialty ,Vincristine ,business.industry ,medicine.medical_treatment ,Immunology ,Phases of clinical research ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Gastroenterology ,Minimal residual disease ,Transplantation ,Maintenance therapy ,Nilotinib ,Internal medicine ,Acute lymphocytic leukemia ,medicine ,business ,medicine.drug - Abstract
We previously reported the interim analysis on the clinical outcome of nilotinib (Tasigna®, Novartis Pharma, Basel, Switzerland), when combined with multi-agent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) in adults. Herein, we reported the final results of the multicenter prospective phase2 trial of Adult Acute Lymphoblastic Leukemia Working Party, the Korean Society of Hematology. Newly diagnosed Ph+ALL patients aged 18 years old or more were eligible when they had adequate organ function. Diagnosis of Ph+ALL was performed via confirmation of the presence of Ph chromosome by conventional GTL-band technique, and/or positive molecular analysis with nested RT PCR for detection of BCR-ABL fusion transcripts. Written informed consent was obtained from all subjects. All patients received induction treatment consisting of vincristine, daunorubicin, oral or parenteral prednisolone, and nilotinib. After achieving complete remission (CR), subjects received either 5 courses of consolidation followed by 2-year maintenance with nilotinib, or allogeneic hematopoietic cell transplantation (alloHCT) depending on the donor availability, his/her tolerability, and patient’s wish. Nilotinib was administered twice a day with a single dose of 400mg (800mg per day) from day8 of induction until the initiation of conditioning for alloHCT or the end of maintenance therapy. Minimal residual disease (MRD) monitoring was performed at the central lab with quantitative RT-PCR assays for peripheral blood BCR-ABL RNA using LightCycler® Technology in serial; at the time of diagnosis, at hematologic CR(HCR), and every 3 months thereafter. BCR-ABL quantification was expressed relative to the amount of glucose-6-phosphate dehydrogenase (G6PDH) mRNA. The molecular response was defined as complete (MCR, MRD-negative) if the BCR-ABL/G6PDH ratio was less than 1x10-6. Toxicity was graded according to National Cancer Institute Common Toxicity Criteria (version 2.0). Subjects had been followed up for 2 years after alloHCT or during maintenance therapy. Data were frozen up in June, 2013. A total of 91 subjects (male: female = 45: 46) were enrolled onto the study between January 2009 and May 2012. The median age was 47 (range 18-71) years old. Type of BCR breakpoint was minor (e1a2) in 71% of patients. The median BCR-ABL/G6PDH ratio was 6.09 (bone marrow) and 3.28 (peripheral blood) at diagnosis. During induction, all subjects required blood product transfusion, and incidence of nonhematologic adverse events (AE) over grade 3 was 17% (jaundice), 18% (ALT elevation), 13% (lipase elevation), and 2% (pancreatitis). Neither QTc prolongation over 500ms nor significant arrhythmia happened among any subject and any cycle. HCR rate was 90% and median time to HCR was 27 days (range, 13-72); most of failure was due to death in aplasia (n=8). MCR rate at HCR was 55%, Cumulative MCR rate was 84%, and median time to MCR was 1.1 months (range, 0.6-15.8). Most common cause of dropout from study was treatment-related death (n=22; during induction/consolidation vs. after alloHCT = 12 vs. 10), and HREL (n=15). Nilotinib was interrupted 75 times among 64 subjects, reduced 14 times among 12 subjects, and discontinued permanently due to hematologic relapse (HREL, n=14), AE (n=6, over gr3:3), and other cause (n=2). Fifty nine patients underwent alloHCT, 34 with myeloablative and 25 with reduced-intensity conditioning. Incidences of acute graft-versus-host disease (GVHD) and chronic GVHD were 41% and 29%, respectively. With a median follow-up of 20.7 months of surviving subjects, estimated hematologic relapse-free survival (RFS), and overall survival (OS) rate at 2 years were 74% and 70%, respectively. Among subject achieving MCR, 2-year molecular RFS rate was 56%. When events were defined as ‘dropout due to AE, isolated molecular / extramedullary relapse, HREL, and death from any cause’, median event-free survival was 12.5 months. In this prospective study, nilotinib was shown to be effective for adult Ph+ALL, and concurrent administration of nilotinib with cytotoxic drug was well-tolerable, although death in aplasia during induction was the most common cause of failure of achieving HCR. In terms of MRD, potential of nilotinib to achieve and maintain MRD negativity were satisfactory (Clinicaltrials.gov NCT00844298). Disclosures: Off Label Use: Nilotinib for Ph+ALL-sientific and academic purpose.
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- 2013
30. Management of Patients After the Failure of Hypomethylating Treatment for Myelodysplastic Syndrome
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Sang Min Lee, Lee Jung-Lim, Jung-Hee Lee, Young-Don Joo, Won Sik Lee, Dae-Young Kim, Kyoo-Hyung Lee, Yunsuk Choi, and Je-Hwan Lee
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Azacitidine ,Chronic myelomonocytic leukemia ,Decitabine ,Salvage therapy ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Chemotherapy regimen ,Surgery ,Transplantation ,Clinical trial ,Internal medicine ,Cytarabine ,medicine ,business ,medicine.drug - Abstract
Abstract 4953 Introduction: Although treatment with hypomethylating agents such as azacitidine or decitabine has been the standard of care for patient with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML), about half of the patients fail to respond to the agents and most responders progress within 2 years. Retrospective studies showed poor outcomes after failure of treatment with azacitidine or decitabine and there is no standard salvage therapy for patients who fail hypomethylating treatment (HMT). We retrospectively studied outcomes of patients who failed HMT and analyzed the effects of salvage therapy after HMT failure. Methods: Between September 2006 and October 2010, a total of 149 patients were treated with either azacitidine (n=75) or decitabine (n=74) for MDS defined by the WHO classification and chronic myelomonocytic leukemia (CMML) in 3 Korean institutes. Ninety-one of the 149 patients were included in this study and disease status at the end of HMT was categorized as stable disease (n=22), primary progression (n=17), progression after response (n=38), and intolerance (n=14). Six patients who were still receiving hypomethylating agents with a median of 19 courses (range, 15 to 48) and 52 patients who stopped hypomethylating agents for other reasons were excluded from the analysis. Results: Median age was 59 years (range, 23 to 80) at the time of HMT failure. Median follow-up duration of surviving patients was 47. 8 months (range, 5. 8 to 62. 9) and 69 patients died. Probability of overall survival (OS) at 3 years was 28. 1% and median OS was 12. 1 months (95% confidence interval [CI], 9. 8 to 14. 4). Multivariate analysis showed that disease status and evolution to acute myeloid leukemia (AML) at HMT failure were independent prognostic factors for OS. A total of 37 patients (40. 7%) received supportive care only after HMT failure and other patients were managed with one or more treatments including immunosuppressive therapy (n=7), low-dose cytarabine (n=9), androgen (n=8), alternate azanucleoside (n=2), intensive chemotherapy (n=24), and allogeneic hematopoietic cell transplantation (HCT) (n=23). Objective response to non-transplant treatment was observed in 11–17% of evaluable patients, while 17 (74%) of 23 patients who received allogeneic HCT attained complete response. Probability of OS at 2 years (from HCT) was 60. 9% in the transplanted patients; it was 78. 6% in patients who received HCT during MDS and 33. 3% in those who received HCT after AML evolution (P=0. 016). Conclusions: The clinical outcomes of patients after hypomethylating treatment failure are poor; especially, AML evolution at the time of hypomethylating treatment failure and primary progression after hypomethylating treatment indicated very poor prognosis. Responses to various low intensity therapies and intensive chemotherapy were infrequent. Long-term survival without disease evidence was observed in about half of the patients who received allogeneic HCT. In appropriately selected patients, allogeneic HCT should be performed in earlier period, especially before evolution to AML. Patients with MDS that has failed to respond to hypomethylating agents should be referred for clinical trials when available. Disclosures: No relevant conflicts of interest to declare.
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- 2012
31. Clinical Effect of High-Dose, Donor-Derived Natural Killer Cells Infused After HLA-Haploidentical Hematopoietic Cell Transplantation
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Dae-Young Kim, Suk Ran Yoon, Mijin Jeon, Kyoo-Hyung Lee, Inpyo Choi, Young-Ah Kang, Sol-Ji Jung, Young-Shin Lee, Hanna Kim, Je-Hwan Lee, Jung-Hee Lee, and Sooyeon Park
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medicine.medical_specialty ,Acute leukemia ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Leukapheresis ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Gastroenterology ,Fludarabine ,Transplantation ,Leukemia ,hemic and lymphatic diseases ,Internal medicine ,medicine ,business ,Diffuse large B-cell lymphoma ,Busulfan ,medicine.drug - Abstract
Abstract 1900 Haploidentical HCT is feasible without ex vivo T cell depletion after conditioning with reduced-dose busulfan, fludarabine, and ATG (Lee K-H, Blood 2011). Furthermore, infusion of donor-derived NK cells (DNKI) after haploidentical HCT has been shown to suppress leukemia recurrence without GVHD in a murine model. Clinically, DNKI up to 2.5×107/kg have been given to patients after haploidentical HCT without obvious increase in GVHD (Yoon SR, BMT 2010). Clinical effect of higher dose of DNKI, however, remains to be studied. Between February 2009 and February 2012, 37 patients with hematologic malignancies (AML, 28; ALL, 7; MDS, 1; DLBCL, 1) underwent haploidentical HCT and received NK cells derived from the same HCT donors twice at 2 (DNKI#1) and 3 weeks (DNKI#2) after HCT. The donors (median age 29 years, range 7–62; offspring 22, siblings 8, and parents 7) underwent 3 to 4 daily leukapheresis after receiving G-CSF. Donated cells during the initial 2 to 3 days were transplanted without further manipulation. Cells collected on the last day were CD3 depleted and differentiated into NK cells ex vivo. In the initial study phase, as per the protocol design, three-patient cohorts each received 0.2×108/kg, 0.5×108/kg, and 1.0×108/kg donor NK cells twice. Among these initial 9 patients, only one patient who received 1.0×108 cells/kg experienced grade-3 acute GVHD. Thereafter, 3 additional patients received 1.0×108 cells/kg twice and none experienced °Ãgrade-3 acute side effect or acute GVHD. For patients enrolled subsequently, donor NK cell doses were based on the quantity of cells generated. The mean viability of final donor NK cell products for DNKIs #1 and #2 were 85% and 71%, respectively; mean CD56+CD122+, 87% and 94%, respectively; and mean CD3+CD56-, 0.4% and 0.3%, respectively, excluding one case with 16% and 7%. The final cell products exhibited additional NK cell features, such as granzyme/perforin gene expression, NK cell receptor expression, TNF-α/IFN-γ production, and cell cytotoxicity against K562 cells. All 37 patients in the study received at least one DNKI. Four patients did not receive the DNKI#2 (3 due to rapid clinical deterioration and 1 due to cell expansion failure). The median cell doses were 1×108/kg (range, 0.2–2.0 ×108/kg) and 1×108/kg (range, 0.2–4.0 ×108/kg) for DNKIs #1 and #2, respectively. In all patients, DNKI was tolerated well without acute toxicities such as fever or hypotension. After HCT, neutrophil engraftment (cumulative incidence, 87%), grade 2–4 acute GVHD (19%), chronic GVHD (27%), and TRM (29%) were observed. The median follow-up period of survivors was 20.0 months (range, 6.2–41.5). Of 33 patients with refractory leukemia (AML, 25; ALL, 7) or lymphoma (n=1), 7 of 25 with AML and 6 of 8 with ALL/lymphoma experienced progression/recurrence of their underlying malignancies (cumulative incidences, 29% vs. 75%; P=0.0325). When considered together with 31 historical patients with refractory acute leukemia (AML 22; ALL 9) treated with haploidentical HCT without high-dose DNKI, univariate analysis showed that the diagnosis (AML vs ALL/lymphoma, P=0.0048), disease status at HCT (primary refractory vs relapse then refractory, P=0.0410), and patient cohort (study vs historical, P=0.0420) were the significant variable predicting less diseases progression/recurrence. Upon multivariate analysis, the diagnosis (AML vs ALL/lymphoma, P=0.005; odd ratio, 0.356; 95% CI, 0.174–0.729) and patient cohort (study vs historical, P=0.033; odd ratio, 0.471; 95% CI, 0.236–0.941) were independent variables predicting less disease progression/recurrence. Kaplan-Meier event-free and overall survival rates for study AML patients, study ALL/lymphoma patients, historical AML patients, and historical ALL patients were 39% and 36%, 0% and 0%, 7% and 0%, and 0% and 0%, respectively. Our study showed that DNKI with median total dose 2×108/kg given over 2–3 weeks after haploidentical HCT was tolerated well without obvious increase in GVHD or TRM. Furthermore, DNKI after haploidentical HCT may decrease leukemia progression especially in patients with refractory AML. Disclosures: No relevant conflicts of interest to declare.
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- 2012
32. A Prospective Randomized Comparison of Idarubicin and High-Dose Daunorubicin in the Induction Chemotherapy for Acute Myeloid Leukemia: An Interim Analysis
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Gyeong Won Lee, Sang Min Lee, Dae-Young Kim, Je-Hwan Lee, Dae Young Zang, Min Kyung Kim, Myung Soo Hyun, Jae-Hoo Park, Won Sik Lee, Hyo Jung Kim, Hun Mo Ryu, Young-Don Joo, Kyoo-Hyung Lee, Jung Lim Lee, Hawk Kim, Sung Hwa Bae, and Jung-Hee Lee
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Acute promyelocytic leukemia ,medicine.medical_specialty ,Daunorubicin ,business.industry ,Immunology ,Induction chemotherapy ,Cell Biology ,Hematology ,medicine.disease ,Interim analysis ,Biochemistry ,Gastroenterology ,Transplantation ,Internal medicine ,medicine ,Cytarabine ,Idarubicin ,business ,Etoposide ,medicine.drug - Abstract
Abstract 3628 Introduction: We conducted a randomized trial comparing two different doses of daunorubicin as induction chemotherapy in young adults with acute myeloid leukemia (AML) and showed intensification of induction therapy using a high daily dose of daunorubicin (90 mg/m2/d × 3d) improved both complete remission (CR) rate and survival duration compared to standard daunorubicin dose (45 mg/m2/d × 3d) (Lee JH et al. Blood 2011;118:3832). Our results confirmed the ECOG work (Fernandez HF et al. N Engl J Med 2009;361:1249). Thus, high-dose daunorubicin (90 mg/m2/d) for 3 days should be the future standard of care for induction of patients with AML. However, it is not known whether a dose of 90 mg/m2/d is superior to a dose of 45–90 mg/m2/d. It is also necessary to compare the effects of high-dose daunorubicin with that of other agents, especially idarubicin. For these reasons, we began another randomized trial comparing two induction regimens in young adults with AML: idarubicin vs. high-dose daunorubicin. This study is now recruiting patients (ClinicalTrials.gov #NCT01145846). Here, we present the results of interim analysis of the study. Methods: This study began on May 2010 and target number of patient's accrual is 300. A total of 161 patients (65 years or younger) with newly diagnosed AML except acute promyelocytic leukemia were registered in this study as of March 22, 2012. Four patients were removed from the study (patient's refusal to be randomized in 2 and change of diagnosis in 2) and the remaining 157 patients were analyzed. After random assignments, 81 patients received idarubicin (AI, 12 mg/m2/d × 3d) and 76 patients received high-dose daunorubicin (AD, 90 mg/m2/d × 3d) in addition to cytarabine (200 mg/m2/d × 7d) for induction of CR. Patients with persistent leukemia received the second attempt of induction chemotherapy, consisting of idarubicin (AI, 12 mg/m2/d × 2d) or daunorubicin (AD, 45 mg/m2/d × 2d) plus cytarabine (5d). Patients who attained CR received 4 cycles of high-dose cytarabine (3 g/m2 × 6 doses) in patients with good- or intermediate-risk cytogenetics and 4 cycles of cytarabine (1 g/m2 × 6d) plus etoposide (150 mg/m2 × 3d) in those with high-risk cytogenetics. Hematopoietic cell transplantation (HCT) was performed according to attending physician's discretion. Results: CR was induced in 123 (78.3%) of 157 patients. Reasons for induction failure were resistant disease in 26, hypoplastic death in 2, and indeterminate cause in 6. As postremission therapy, 3 patients received no further treatment, 35 received consolidation chemotherapy without HCT, 73 underwent allogeneic HCT, and 12 underwent autologous HCT. The CR rates were not significantly different between two arms: 77.8% (63 of 81, AI) vs. 78.9% (60 of 76, AD) (P=0.859). With a median follow-up of 285 days, overall survival probabilities at 18 months were 65.6% in AI vs. 72.6% in AD (P=0.278). The probabilities at 18 months for relapse-free survival were 78.5% in AI vs. 86.2% in AD (P=0.563) and those for event-free survival were 61.5% in AI vs. 67.7% in AD (P=0.078). Toxicity profiles were similar between two arms. Conclusions: The results of interim analysis of this ongoing phase 3 trial, which compares idarubicin (12 mg/m2/d × 3d) with high-dose daunorubicin (90 mg/m2/d × 3d), did not show significant differences in the outcomes of patients. It appears that the effects of two drugs with the doses in current study are equivalent as an induction chemotherapeutic agent in regards to CR rates and overall, relapse-free or event-free survivals. Disclosures: No relevant conflicts of interest to declare.
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- 2012
33. Nilotinib Combined with Multi-Agent Chemotherapy for Adult Patients with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Interim Results of Korean Adult ALL Working Party Phase 2 Study
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Deok-Hwan Yang, Jae Hoon Lee, Jung-Hee Lee, Hawk Kim, Je-Hwan Lee, Yeung-Chul Mun, Dae-Young Kim, Sang Kyun Sohn, Won Sik Lee, Kyoo-Hyung Lee, Je-Jung Lee, Jong Ho Won, Dong Hwan Kim, Young Don Joo, Hyun-Sook Chi, Myung Soo Hyun, Sung-Soo Yoon, Inho Kim, Yang Soo Kim, and Chul Won Jung
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medicine.medical_specialty ,Vincristine ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Interim analysis ,Biochemistry ,Gastroenterology ,Chemotherapy regimen ,Surgery ,Transplantation ,Imatinib mesylate ,Maintenance therapy ,Nilotinib ,Acute lymphocytic leukemia ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
Abstract 1517 Background: Incorporation of imatinib into classical cytotoxic chemotherapy has improved the response and survival of patients with Philadelphia chromosome-positive (Ph+) adult acute lymphoblastic leukemia (ALL). Nilotinib (Tasigna, Novartis Pharma, Basel, Switzerland), a second-generation tyrosine kinase inhibitor with enhanced in-vitro inhibition of BCR-ABL kinase, showed faster and deeper responses than imatinib among patients with chronic myeloid leukemia. Moreover, less serious gastrointestinal adverse effects of nilotinib may be beneficial to combination with intensive chemotherapy in Ph+ ALL when compared with imatinib. Herein, we report interim results of a prospective single-arm multicenter phase-2 study evaluating the safety and efficacy of nilotinib-combined multi-agent chemotherapy in Ph+ ALL. Methods: Patients aged over 18 years old were eligible if they had newly diagnosed Ph+ ALL, and adequate hepatic/renal/cardiac function. Diagnosis of Ph+ ALL was dependent upon confirmation of t(9;22) with cytogenetics by conventional GTL-band technique, and/or positive molecular analysis with nested RT PCR for detection of BCR-ABL fusion transcripts. Written informed consent was obtained from all patients. All patients received induction treatment consisting of vincristine, daunorubicin, oral prednisolone, and nilotinib. After achieving complete remission (CR), patients received either 5 courses of consolidation followed by 2-year maintenance with 6-mercaptopurine plus methotrexate, or allogeneic hematopoietic cell transplantation (alloHCT) according to the donor availability and his/her general condition. Nilotinib was administered twice a day with a single dose of 400mg (800mg per day) from day8 of induction until the initiation of alloHCT or the end of maintenance therapy. Quantitative RT-PCR assays were performed at the central lab with Light-Cycler Technology at the time of diagnosis, at CR, and every 3 months thereafter. BCR-ABL quantification was expressed relative to the amount of glucose-6-phosphate dehydrogenase (G6PDH) mRNA. The molecular response was defined as complete (MCR) if the BCR-ABL/G6PDH ratio was less than 1×10−6. Toxicity was graded according to National Cancer Institute Common Toxicity Criteria (version 2.0). For interim analysis, outcome was updated as of July 1, 2011. Results: A total of 50 consecutive patients (male: female = 22: 28) were enrolled onto the study between January 2009 and December 2010. The median age was 44.5 (range 18–71) years old. Type of BCR breakpoint was minor (e1a2) in 66% of patients. The median BCR-ABL/G6PDH ratio was 6.09 (bone marrow) and 3.08 (peripheral blood) at the diagnosis. Except five patients who died in aplasia during induction, 45 (90%) patients achieved hematologic remission (HCR), and MCR rate was 54% at the time of HCR. During the whole treatment periods, administration of nilotinib was interrupted 50 times among 30 patients, and dose was reduced among 6 ones. Of 45 patients who achieved HCR, median dose intensity (DI) of nilotinib between day8 and day of confirmation of HCR was 769.2mg (range 160–800), and MCR rates were not different among two subgroups when dichotomized using the median dose intensity (60.9% vs. 59.1%). During the induction, 20% of patients experienced ≥grade 3 jaundice, which were all reversible, and 2% experienced pancreatitis. Thirty three patients underwent alloHCT, 19 with myeloablative and 14 with non-myeloablative conditioning. Incidences of ≥grade 3 acute graft-versus-host disease (GVHD) and extensive chronic GVHD were 9% and 3%, respectively. With a median follow-up of 17.4 months (range, 6.9–29.1), estimated relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS) at 2 years were 71.1%, 49.4%, and 66.2%, respectively. Of 33 patients who underwent alloHCT, 2-year RFS, EFS, and OS rate were 70.5%, 60.0%, and 83.2%, respectively. Achievement of MCR and DI of nilotinib were not associated with outcome. Conclusion: Nilotinib was tolerable in combination with intensive chemotherapy for adult patients with Ph+ ALL, and the outcomes were comparable to previous results based on imatinib combination. Patient recruitment is ongoing currently based on this interim analysis, and the final results are expected in 2014. Disclosures: Off Label Use: Nilotinib is used as 'off-label drug' for Philadelphia chromosome-positive acute lymphoblastic leukemia in this trial. We have achieved the permission for the use of this drug in this clinical trial from the Korean FDA.
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- 2011
34. Comparative Analysis on Cellular Components of Bone Marrow Microenvironment in Normal and Aberrant Hematopoiesis
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Hyun-Sook Chi, Young-Ho Lee, Young-hee Kwon, Jung-Hee Lee, Chan-Jeoung Park, Dae-Young Kim, Chan-Hee Yoon, Je-Hwan Lee, Kyoujung Hwang, Byung-Bae Park, Kyoo-Hyung Lee, Hyunju Jun, and Seongsoo Jang
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Stromal cell ,T cell ,Immunology ,CD34 ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Haematopoiesis ,medicine.anatomical_structure ,medicine ,Cancer research ,Osteocalcin ,biology.protein ,Cytotoxic T cell ,Bone marrow ,Stem cell - Abstract
Abstract 4808 Background: It is now evident that hematopoietic stem cells (HSCs) reside preferentially at the endosteal region within the bone marrow (BM) where bone-lining osteoblasts are a key cellular component of the HSC niche that directly regulates HSC fate. We investigated the microenvironmental differences including osteoblastic activities and HSC components in myeloproliferative (chronic myeloid leukemia, CML) and hypogenerative disease (aplastic anemia, AA) as well as normal control (NC). Methods: The immunohistochemistry for osteonectin, osteocalcin, stromal cell derived factor (SDF, CXCL12), T cell, T helper/inducer cell, T suppressor/cytotoxic cell, hematopoietic stem/progenitor (CD34, CD117) and megakaryocytes was performed on BM biopsy specimens from 10 AA patients, 10 CML patients and 10 NC (lymphoma without BM involvement). The positive cells for immunohistochemical stainings except osteocalcin on each slide were calculated on 10 high power fields (HPF, ×400), and then corrected by the cellularity. The positive cells for osteocalcin were counted on the peritrabecular line on each slide, and then corrected by the mean length measured. Results: The CD34+ cells (p=0.012) and megakaryocytes (p Conclusions: Cellular components of BM microenvironment in 2 hematologic diseases representative of myeloproliferation (CML) and hyporegeneration (AA) respectively are quite different. Further studies would be required to explore the role of these components for hematopoiesis and the rationale for therapeutic application. Disclosures: No relevant conflicts of interest to declare.
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- 2011
35. Prognostic Implications of CD14 Positivity in Acute Myeloid Leukemia Arising From Myleodysplastic Syndrome
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Jae Seok Lee, Sung-Doo Kim, Ahrang Jung, Miee Seol, Young-Shin Lee, Kyoo-Hyung Lee, Young-Ah Kang, Young-Hun Park, Dae-Young Kim, Mijin Jeon, Jung-Hee Lee, Je-Hwan Lee, and Yunsuk Choi
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Oncology ,medicine.medical_specialty ,Univariate analysis ,Daunorubicin ,business.industry ,Immunology ,CD34 ,Induction chemotherapy ,Cell Biology ,Hematology ,Biochemistry ,Surgery ,Transplantation ,Immunophenotyping ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Cytarabine ,Idarubicin ,business ,medicine.drug - Abstract
Abstract 3523 Introduction: Secondary AML that has evolved from MDS shows different clinical features and outcomes compared to de novo AML. Prognostic implications of immunophenotypes have been studied in de novo AML, whereas those have not well been defined in secondary AML from MDS. Methods: This retrospective study involved analysis of data from 65 adult patients, 37 males and 28 females, who were diagnosed with AML arising from MDS at a single institute. Data for baseline clinico-pathological features, treatments, and outcomes were collected from medical records of each patient. Immunophenotyping was performed for the markers including TdT, CD34, CD13, CD33, CD117, CD14, CD56, HLA-DR, CD3, CD7, CD10, and CD19 using flow cytometry. Results: At the time of MDS diagnosis, the WHO subtype was RA/RARS in 5, RCMD in 10, RAEB-1 in 17, RAEB-2 in 29, and unknown in 4. For the treatment of MDS, hypomethylating agents were given to 17 patients and 2 patients underwent allogeneic hematopoietic cell transplantation (HCT). Median duration of MDS prior to diagnosis of AML was 4.9 months (range, 0.3–91.1). At the time of AML evolution, median age was 50.7 years (range, 18–80), and cytogenetic risk group was good-risk in 1, intermediate-risk in 45, and poor-risk in 18. Proportion of positivity of each immunophenotype marker was as follows: TdT (5%), CD34 (65%), CD13 (98%), CD33 (97%), CD117 (90%), CD14 (22%), CD56 (10%), HLA-DR (93%), CD3 (2%), CD7 (35%), CD10 (8%), and CD19 (2%). After the evolution to AML, 52 patients received induction chemotherapy consisted of cytarabine plus idarubicin or daunorubicin and 8 patients underwent allogeneic HCT as initial treatment of AML. Complete remission (CR) was induced in 27 patients after treatment. At a median follow-up time of 29.2 months (range, 2.6–116.2) among surviving patients, 49 patients died, 13 relapsed, and 53 died or relapsed. Median overall survival (OS), relapse-free survival (RFS), and event-free survival (EFS) were 7.6, 26.1, and 5.4 months, respectively. Of immunophenotype markers, CD14 positivity only showed prognostic implications at the univariate analyses: lower CR rate after induction chemotherapy (P=0.034) and shorter survivals (OS, P Conclusions: Surface expression of CD14 on leukemic blasts was an independent prognostic factor for survivals in the patients with AML arising from MDS. Disclosures: No relevant conflicts of interest to declare.
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- 2011
36. Immediate Allogeneic Hematopoietic Cell Transplantation (HCT) in Acute Myeloid Leukemia (AML) Arising From Myelodysplastic Syndrome (MDS)
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Yunsuk Choi, Jung-Hee Lee, Young-Hun Park, Je-Hwan Lee, Young-Shin Lee, Young-Ah Kang, Sung-Doo Kim, Ahrang Jung, Kyoo-Hyung Lee, Dae-Young Kim, Mijin Jeon, Miee Seol, and Jae Seok Lee
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Oncology ,medicine.medical_specialty ,Daunorubicin ,business.industry ,medicine.medical_treatment ,Immunology ,Induction chemotherapy ,Retrospective cohort study ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Biochemistry ,Chemotherapy regimen ,Surgery ,Transplantation ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Cytarabine ,Idarubicin ,business ,medicine.drug - Abstract
Abstract 2031 Introduction: Treatment of secondary AML arising from MDS is unsatisfactory. Induction rate of complete remission (CR) is low with standard inuction chemotherapy regimen and relapse is common without allogeneic HCT. Immediate allogeneic HCT without induction chemotherapy can be an option if an appropriate donor is available in patients whose disease progress into AML from MDS. We intended to analyze the benefit of immediate allogeneic HCT versus induction chemotherapy in patients with AML arising from MDS. Methods: Between 1991 and 2010, 95 patients were diagnosed with AML that had evolved from antecedent MDS. After the diagnosis of AML, 10 patients received supportive care only. This retrospective study involved analysis of data from remaining 85 patients; 11 proceeded to immediate allogeneic HCT without induction chemotherapy (HCT group) and 74 were treated with induction chemotherapy (IC group). The clinical outcomes between the HCT group and the IC group were compared. Results: Median age was 48 years (range, 18–78). Patient characteristics at the time of AML diagnosis were similar between the HCT and IC groups except total leukocyte counts, which were higher in the IC group than the HCT group (P=0.009). Patients in the IC group were initially treated with induction chemotherapy consisted mostly of cytarabine plus daunorubicin or idarubicin, while those in the HCT group received allogeneic HCT from HLA matched sibling donors (n=7) or unrelated volunteers (n=4). Thirty-one patients (41.9%) in the IC group achieved CR with induction chemotherapy, whereas 9 (81.8%) in the HCT group achieved CR after HCT (P=0.013). Of 74 patients in IC group, 28 underwent allogeneic HCT in their disease status of the first CR (n=13), primary refractory disease (n=10), or the first or second relapse (n=5). The median follow-up duration for surviving patients was 8.2 months (range, 0.2–171.3). During this time, 62 patients died, 16 relapsed after CR, and 68 died or relapse. The median overall survival (OS) and event-free survival (EFS) were 8.3 and 6.4 months, respectively. Relapse probability at 5 years was 49.2%. The HCT group showed a significantly longer EFS than did the IC group (median 29.2 vs. 5.2 months, P=0.042). OS of the HCT group was higher than that of the IC group, but the difference was not statistically significant (median 34.6 vs. 7.6 months, P=0.149). Relapse probability was not significantly different between the two groups (35.7% vs. 53.1% at 5 years, P=0.278). After adjustment for other variables, the HCT group showed significantly better outcomes than did the IC group in terms of CR rate (HR, 11.195; 95% CI, 1.940–64.619; P=0.007) and EFS (HR, 0.384; 95% CI, 0.163–0.905; P=0.029). Conclusions: Immediate allogeneic HCT is a viable option in AML arising from MDS if an appropriate donor is available. Disclosures: No relevant conflicts of interest to declare.
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- 2011
37. Retrospective Comparison of Azacitidine and Decitabine in the Treatment of Myleodysplastic Syndrome
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Sang Min Lee, Jung Lim Lee, Young-Don Joo, Yunsuk Choi, Jae Seok Lee, Jung-Hee Lee, Dae-Young Kim, Won Sik Lee, Young-Hun Park, Kyoo-Hyung Lee, Sung-Doo Kim, and Je-Hwan Lee
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Oncology ,Cytopenia ,medicine.medical_specialty ,business.industry ,Immunology ,Azacitidine ,Chronic myelomonocytic leukemia ,Decitabine ,Subgroup analysis ,Cell Biology ,Hematology ,Pharmacology ,Neutropenia ,medicine.disease ,Biochemistry ,Hypomethylating agent ,Internal medicine ,Medicine ,business ,Adverse effect ,medicine.drug - Abstract
Abstract 3809 Introduction: Two DNA methyltransferase inhibitors, azacitidine and decitabine, are currently approved for the treatment of myleodysplastic syndrome (MDS) according to the results of several Phase II and III trials, which have demonstrated the efficacy of the agents. Despite widespread clinical use of DNA methyltransferase inhibitors, one of important practical issues is which drug should be chosen. In this retrospective study, we tried to compare azacitidine and decitabine for the treatment of MDS in regards to treatment response, toxicities, and survival. Methods: Between September 2006 and October 2010, a total of 149 patients were treated with either azacitidine (n=75) or decitabine (n=74) for MDS defined by the WHO classification and chronic myelomonocytic leukemia (CMML) in 3 Korean institutes; all are included in this analysis. Azacitidine 75 mg/m2/day was administered as a subcutaneous injection for 7 consecutive days and decitabine 20 mg/m2/day as a 1-hour intravenous infusion for 5 consecutive days. Both agents were repeated every 4 weeks. Treatment response was evaluated using modified International Working Group response criteria. Results: Median age of the patients, 100 males and 49 females, was 60 years (range, 23–83). WHO subtype at the time of decitabine treatment was RA in 18, RARS in 2, RCMD in 28, RCRS in 5, RAEB-1 in 46, RAEB-2 in 39, unclassified in 2, and CMML in 9. IPSS risk category was low/intermediate-1 in 72 and intermediate-2/high in 72. Median number of courses delivered to each patient was 5 (range, 1–31) for azacitidine and 4 (range, 1–24) for decitabine (P=0.033). Hematologic responses (CR/PR/mCR) were induced in 9 patients (12.0%) with azacitidine and in 22 (29.7%) with decitabine (P=0.008). The rates of overall response (CR/PR/mCR/HI) was not significantly different between azacitidine (52.0%) and decitabine (63.5%) (P=0.155). Median number of treatment courses to achieve any response was 2 (range, 1–6) for azacitidine and 1 (range, 1–5) for decitabine (P=0.269). Adverse events were evaluated for the first 6 courses for all patients, for a total of 584 courses. Major adverse events were cytopenia and cytopenia-related infection. Grade 3 or higher neutropenia was more frequent with decitabine (79.6%) than with azacitidine (72.2%) (P=0.040), but incidence of febrile episode requiring intravenous antibiotics was similar (12.4% with decitabine vs. 15.4% with azacitidine, P=0.298). Grade 3 or higher non-hematologic toxicities were infrequent and reversible with both agents. Median follow-up duration of surviving patients was 46.9 months (range, 11.8–55.5) for azacitidine and 22.7 months (range 3.3–33.3) for decitabine. Probabilities of overall survival (OS) at 2 years were 43.5% for azacitidine, and 55.5% for decitabine. The difference of OS in favor of decitabine over azacitidine was significant after adjustment for other variables (HR, 0.539; 95% CI, 0.325–0.895; P=0.017). Subgroup analysis showed that the survival superiority of decitabine over azacitidine was evident principally in patients with IPSS low/intermediate-1 (HR, 0.131; P=0.006), MDS duration of 1 year or less (HR, 0.534; P=0.022), or ECOG performance scale of 0–1 (HR, 0.589; P=0.060). In contrast, a tendency was noted for survival superiority of azacitidine over decitabine in patients with MDS duration over 1 year (HR, 2.107; P=0.235) or ECOG scale of 2–3 (HR, 2.492; P=0.074). Conclusions: Although both azacitidine and decitabine were effective in the treatment of patients with MDS, there were some differences between two agents in regards to response patterns, toxicities, and type of subgroups that showed more beneficial effects with the hypomethylating agent. Disclosures: No relevant conflicts of interest to declare.
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- 2011
38. Hepatic Sinusoidal Obstruction Syndrome After Allogenetic Hematopoietic Stem Cell Transplantation in Adult Acquired Aplastic Anemia
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Chul Won Jung, Sung-Soo Yoon, Byung Soo Kim, Young Don Joo, Ho-Jin Shin, Deog-Yeon Jo, Sang Kyun Sohn, Jae Hoo Park, Hawk Kim, Kyoo-Hyung Lee, Jong Ho Won, Sung-Hwa Bae, and Sung-Hyun Kim
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medicine.medical_specialty ,Cyclophosphamide ,business.industry ,medicine.drug_class ,medicine.medical_treatment ,Immunology ,Horse ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Biochemistry ,Gastroenterology ,Fludarabine ,Surgery ,Regimen ,Internal medicine ,Medicine ,Corticosteroid ,Methotrexate ,business ,Busulfan ,medicine.drug - Abstract
Abstract 3012FN2 The hepatic sinusoidal obstruction syndrome (SOS; veno-occlusive disease [VOD]) is an acute complication after allogeneic hematopoietic stem cell transplantation (alloHSCT). However, the actual incidence and outcomes after alloHSCT in patients with adult acquired aplastic anemia (AA) was not defined yet. We investigated the incidence, risk factors and outcomes of SOS in AA. Data was taken from our previous retrospective study comparing matched sibling donors versus alternative donors (KSBMT07-02 study) and prospective randomized phase III study comparing cyclophosphamide (Cy)-ATG and Cy-fludarabine (Flu)-ATG (COSAH C-004A study) in patients with adult acquired AA. Total 260 patients were included in this analysis. SOS developed in 7.3% (n=19/260). SOS patients were male in 13 (68.4%), related donors in 84.2%, HLA full-matched in 73.7%, same donor-recipient sex matching in 63.2% patients. There were no TBI containing conditioning regimen and all patients received Cy containing conditioning regimen. The majority (94.7%) received ATG as condition regimen; horse ATG in 73.7% and rabbit ATG in 21.1% patients. Classical Cy (200mg/m2)-ATG was the most common conditioning regimen (84.2%). Sixteen patients (84.2%) received preventive medication of SOS and the major drug was heparin (78.9%). Among the diagnostic criteria of SOS, weight gain was observed in 17 (89.5%); hepatomegaly in 14 (73.7%); hyperbilirubinemia in 17 (89.5%) patients. The average total bilirubin was 6.65 (range 1.8–26.9) mg/dL. The severity of SOS was mild in 10 (52.6%), moderate in 6 (31.6%) and severe in 3 (15.8%) patients. Treatment for SOS were supportive care (72.2%), UDCA (16.7%) and corticosteroid (11.1%). All severe cases died of SOS and one moderate case died of multiple organ failure combined with infection without recovery of SOS. Therefore the mortality of SOS was 4/19 (21.1%). The probability of mortality by SOS had no correlation with weight gain (p=1.000), hepatomegaly (p=0.524), hyperbilirubinemia (p=1.000), maximal total bilirubin (p=0.239) or maximal direct bilirubin value (p=0.184). The frequencies of SOS were not significant in male (p=0.126), older than 31y (p=9.8%), prior IST (n=10/116, 8.6%; p=0.465), prior ATG usage for IST (p=0.846), unrelated donor (p=0.216), HLA mismatch (p=0.340), female to male matching (n=3/46, 6.5%; p=0.935), ABO incompatible (n=10/125, 8.0%; p=0.680), TBI conditioning (p=0.232), cyclophosphamide (p=1.000), ATG conditioning (p=0.325), fludarabine condition (p=0.221), busulfan conditioning (p=1.000), cyclosporine prophylaxis for GvHD (p=0.272), methotrexate prophylaxis for GvHD (p=0.170), bone marrow as a stem cell source (p=1.000). However, Cy 200mg/m2 conditioning (p=0.035), classical Cy-ATG condition (p=0.007) and horse ATG conditioning (p In conclusion, SOS is a relatively rate acute complication of alloHSCT in AA (7.3%). However the mortality of SOS is still high under supportive care. Horse ATG conditioning regimen was a significant risk factor for developing SOS. Disclosures: No relevant conflicts of interest to declare.
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- 2011
39. Hematologic Improvement with Iron Chelation using therapy Deferasirox in Patients with Aplastic Anemia: A Subgroup Analysis of KAMS0112 Prospective Study
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Byung Soo Kim, Ho Young Kim, Hwi-Joong Yoon, Myung Soo Hyun, Chul Soo Kim, Jong Ho Won, Hyeok Shim, Chul Won Jung, Deog-Yeon Jo, Sang Kyun Sohn, Hyeoung Joon Kim, Joo-Seop Chung, Jae Hoon Lee, Yoo Hong Min, Kyoo-Hyung Lee, Jae Yong Cho, Mark Hong Lee, Sung-Soo Yoon, Young-Don Joo, Chu-Myung Seung, and June-Won Cheong
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medicine.medical_specialty ,Cytopenia ,Anemia ,business.industry ,medicine.medical_treatment ,Immunology ,Deferasirox ,Bone marrow failure ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Gastroenterology ,Transplantation ,Internal medicine ,medicine ,Aplastic anemia ,Prospective cohort study ,business ,medicine.drug - Abstract
Abstract 3424 Patients with aplastic anemia (AA) are suffered from various complications related to bone marrow failure and peripheral cytopenia. Although immunosuppressive therapy or hematopoietic stem cell transplantation has been performed for curative purpose, the majority of patients have been treated only by supportive cares including repeated transfusion. However, because continued transfusion eventually induces iron overload in many tissues and organs, transfusional iron overload and its consequences are another life-threatening problems for AA patients. Previous reports about iron chelation therapy (ICT) have mainly shown its efficiency for decreasing tissue iron and safety. However, improvement in hematopoiesis after iron chelation therapy has been limitedly reported as case reports or trials involving small number of patients without objective tools for measuring tissue iron content. In the KAMS0112 study (a multi-center, open label, prospective study evaluating the efficacy of ICT with deferasirox in transfusional iron overload with myelodysplastic syndrome or AA using quantitative R2-MRI, Ferriscan), a total of 54 patients with AA showing serum ferritin level over 1,000 ng/ml were enrolled from 19 institutes, and further analyzed for the changes in hemogram during ICT as well as efficacy and safely of deferasirox. During the study, the specific treatments for AA, such as immunosuppressive therapy or hematopoietic stem cells transplantation, were not undertaken. During 1 year prior to study, patients received 23.7±16.9 units of red blood cell (RBC) product, and the baseline serum ferritin level and liver iron content (LIC) were 4,164±447 ng/ml and 20.1±12.0 mg Fe/g DW, respectively. Deferasirox was given orally at a dose of 20 mg/kg/day for at least 6 months to all patients. If the serum ferritin level falls below 500 ng/ml, treatment was withheld. In spite of continued transfusional support during the study, serum ferritin level and LIC were significantly decreased after 1 year of ICT with deferasirox (Ds-ferritin=−3,076.7±489.9 ng/ml, p=0.0003; DLIC=−7.73 mg/Fe/g DW, p=0.001). To evaluate the improvement of each parameter in hemogram by ICT, patients with baseline hemoglobin level less than 8.0 g/dl (n=28), with baseline WBC count less than 4/ml (n=43), and with baseline platelet count less than 20/ml (n=31) were selected separately. At the end of study, hemoglobin level and platelet count (8.2±3.0 g/dl and 22.2±31.4/ml, respectively) was significantly increased from the baseline value (6.1±1.1 g/dl, p=0.001; 12.5±12.4/ml, p=0.05, respectively). WBC count was also slightly increased (from 2.1±0.9/ml to 2.3±0.9/ml, p=0.457). Considering the relatively uniform criteria of transfusion, the finding that hemoglobin level and platelet count could increase above 8 g/dl and 20/ml, respectively, after 1 year of deferasirox treatment is clinically significantly. Due to gradual improvement of anemia, requirement of RBC transfusion had continuously decreased during the study period (R2=0.31). This subanalysis of KAMS0112 study demonstrates that ICT using deferasirox can be effective in improving anemia and thrombocytopenia in the transfusional iron overload patients with AA, as well as reducing serum ferritin level and LIC. Further studies might be required to elucidate the mechanism involved in the improvement of hematopoiesis associated with correction of deranged intracellular iron homeostasis. Disclosures: Min: Novartis: Research Funding. Yoon:Novartis: Research Funding. Kim:Novartis: Research Funding. Lee:Novartis: Research Funding. Lee:Novartis: Research Funding. Won:Novartis: Research Funding. Shim:Novartis: Research Funding. Kim:Novartis: Research Funding. Seung:Novartis: Research Funding. Kim:Novartis: Research Funding. Lee:Novartis: Research Funding. Chung:Novartis: Research Funding. Hyun:Novartis: Research Funding. Jo:Novartis: Research Funding. Jung:Novartis: Research Funding. Sohn:Novartis: Research Funding. Yoon:Novartis: Research Funding. Kim:Novartis: Research Funding. Joo:Novartis: Research Funding. Cheong:Novartis: Research Funding.
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- 2011
40. Validation of New Prognostic Model Including Comorbidities in Patients with Myleodysplastic Syndrome Receiving Hypomethylating Therapy
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Yunsuk Choi, Dae-Young Kim, Jung-Hee Lee, Sang Min Lee, Sung-Doo Kim, Young-Hun Park, Young-Don Joo, Kyoo-Hyung Lee, Won Sik Lee, Je-Hwan Lee, and Jae Seok Lee
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medicine.medical_specialty ,business.industry ,Immunology ,Azacitidine ,Chronic myelomonocytic leukemia ,Decitabine ,Cancer ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Comorbidity ,Surgery ,Internal medicine ,medicine ,Hypomethylating Therapy ,Prognostic model ,In patient ,business ,medicine.drug - Abstract
Abstract 1708 Introduction: A new prognostic model including comorbidities, which are assessed using the Adult Comorbidity Evaluation-27 (ACE-27), was proposed for the patients with MDS by researchers from MD Anderson Cancer Center, Houston, TX (J Clin Oncol 2011;29: 2240). The model was developed after analysis of 600 patients who presented to the center. We aimed to validate the new prognostic model for the Korean patients with MDS who were treated with hypomethylating agents. Methods: Between September 2006 and October 2010, 149 patients were treated with either azacitidine or decitabine for MDS defined by the WHO classification and chronic myelomonocytic leukemia (CMML) in 3 Korean institutes. The new prognostic model included age (> 65 years, 2 score points), comorbidity assessed by ACE-27 (mild/moderate, 1 point; severe, 3 points), and IPSS (intermediate-2, 2 points; high, 3 points). Patients were divided into one of 3 risk groups: low (score 0–1), intermediate (scores 2–4), and high (scored 5–8). Risk group by the new prognostic model could not be assigned in 10 patients, thus a total of 139 patients were included in this analysis. Azacitidine 75 mg/m2/day was administered as a subcutaneous injection for 7 consecutive days (n=68) and decitabine 20 mg/m2/day as a 1-hour intravenous infusion for 5 consecutive days (n=71). Both agents were repeated every 4 weeks. Clinico-patholoical data including comorbidities were collected at time of hypomethylating therapy. Treatment response was evaluated using modified International Working Group response criteria. Results: Median age was 61 years (range, 23–83); 47 patients were over 65 years old. Overall comorbidity score assessed by ACE-27 was as follows: none (n=65), mild (n=53), moderate (n=15), and severe (n=6). IPSS risk category was low/intermediate-1 in 72, intermediate-2 in 55, and high in 12. Risk group measured by the prognostic model was low in 42 (30.2%), intermediate in 79 (56.8%), and high in 18 (12.9%). Hypomethylating therapy induced hematologic responses (CR/PR/mCR) in 28 patients (20.1%) and rate for overall responses (CR/CR/mCR/HI) was 57.6% (80/139). The treatment responses were not significantly different between 3 risk groups. At a median follow-up time of 27.0 months (range, 3.3–55.5) among surviving patients, 70 patients died and overall survival (OS) probability was 49.5% at 2 years; median OS was 24.1 months (95% CI, 11.7–36.5). OS was significantly different according to the presence of comorbidities (OS at 2 years, none vs. mild/moderate vs. severe, 63.4% vs. 37.5% vs. 33.3%, P=0.006) or risk groups by the prognostic model (OS at 2 years, low vs. intermediate vs. high, 71.1% vs. 46.1% vs. 18.5%, P Conclusions: The new prognostic model including comorbidities assessed by ACE-27 was useful to predict overall survival in patients with MDS receiving azacitidine or decitabine, although the model could not predict response to the hypomethylating agents. Disclosures: No relevant conflicts of interest to declare.
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- 2011
41. Biweekly Gemcitabine-Oxaliplatin and Dexamethasone for Relapsed/Refractory Malignant Lymphoma
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Jung Lim Lee, Dae-Young Kim, Hun-Mo Ryoo, Hawk Kim, Won-Sik Lee, Sung Hwa Bae, Jae Hoo Park, Jung-Hee Lee, Young Don Joo, Kyoo Hyung Lee, and Je-Hwan Lee
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medicine.medical_specialty ,business.industry ,Immunology ,Phases of clinical research ,Combination chemotherapy ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Chemotherapy regimen ,Gastroenterology ,Gemcitabine ,Surgery ,Oxaliplatin ,Transplantation ,Regimen ,Internal medicine ,medicine ,business ,Progressive disease ,medicine.drug - Abstract
Abstract 4952 Gemcitabine (GEM) and oxaliplatin (OX) are commonly used as weekly or biweekly therapy. In this regard, dose dense biweekly schedule seems of reasonable investigational value in GEM and OX combination for non-Hodgkin lymphoma (NHL). We conducted phase II study to evaluate the efficacy of the combination chemotherapy consisting of GEM, OX and dexamethasone (GemDOx) as a biweekly regimen in patients with relapsed or refractory NHL. Primary end point was objective response rate and secondary end points were toxicities, progression-free survival, overall survival, ASCC efficacy, rate for proceeding to ASCT. The inclusion criteria were relapsed or refractory malignant aggressive NHL of any histological subtypes: Patients who have refractory to first-line CHOP-like regimen; Patients who have first relapsed after first-line CHOP-like regimen or upfront autologous or allogeneic hematopoietic stem cell transplantation Chemotherapy was repeated every 4 weeks. Gemcitabine 1000 mg/m2 in NS 500 mL was administered IV as a fixed dose rate infusion (FDRI, 10 mg/m2/min) on days 1 and 15. OX 85 mg/m2/d in 5DW 500 mL was administered IV over 6 hour on day 1 and 15. Dexamethasone 40 mg was admistered orally on day 1 through 4. All 29 patients were enrolled in this phase II study. Patients were male in 18 (62.1%), DLBCL in 16 (55.2%), stage III/IV in 25 (79.3%) and relapsed NHL in 23 (79.3) patients. Five (17.2%) patients had relapsed after upfront autologous/allogeneic stem cell transplantation. The most common prior chemotherapy was R-CHOP (n=16, 55.2%) and 17 (58.6%) were exposed to rituximab as prior chemotherapy. The median age and median prior chemotherapy were 53 (range 26–74) years old and 1 (range 1–4) cycle, respectively. IPI at relapse were 3/4 in 11 (37.9%). Only 17 (58.6%) and 9 (31.0%) patients could finish 2 or more and 4 or more cycles, respectively, and median received cycle was 2 (range 0.5–8). Four patients completed planned all 6 or more cycles, and 4 patients stopped GemDOx after 4 cycles for ASCT, and 1 patient lost initial response and progressed after 4 cycles. The reasons of drop-out were progressed disease in 15 (51.7%), lost to follow-up in 4 (13.8%), discrete of attending physician in 1 (3.4%) and withdraw of consent in 1 (3.4%). Maximal response rate was 27.9% (CR in 13.8%; PR in 13.8%) in intent-to-treat basis and 47.0% (CR in 23.5% and PR in 23.5%) among patients who had received at least 2 cycles of GemDOx. Stable disease was observed in 6 (20.7%) in intent-to-treat basis and 5 (29.4%) among patients who had received at least 2 cycles of GemDOx. Among patients who received 2 or more cycles, ORR was 53.4% (CR in 26.7% and PR in 26.7%) in relapsed NHL and 0% (SD in 50% and PD in 50%) in refractory NHL. Median survival and median progression-free survival were 20.526 (95% CI, 8.945–32.108) and 3.947 (95% CI, 0–10.358), respectively in all patients (Figure 1). Among patients who had completed 2 or more cycles, median survival and median progression-free survival were not reached and 10.625 (95% CI, 0–21.575), respectively. In conclusion, dose-dense biweekly GemDOx showed activity against highly unfavorable relapsed NHL, but failed to show superior overall response rate especially against refractory NHL. The main cause of failure was progressive disease although considering high drop-out rate. Disclosures: No relevant conflicts of interest to declare.
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- 2011
42. Dasatinib for Chronic Phase Chronic Myeloid Leukemia After Failure of Imatinib In Korean Patients
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Dong Hwan Kim, Seok Kim, Jun Ho Jang, Myung-Hee Chang, Sung-Soo Yoon, Joo-Seop Chung, Sang Kyun Sohn, Kihyun Kim, Won Seog Kim, Hyeoung Joon Kim, Kyoo-Hyung Lee, Chul Won Jung, and Ha Yeon Lee
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medicine.medical_specialty ,business.industry ,Immunology ,Imatinib ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Biochemistry ,Rash ,Gastroenterology ,Surgery ,Dasatinib ,Imatinib mesylate ,Tolerability ,Median follow-up ,hemic and lymphatic diseases ,Internal medicine ,medicine ,medicine.symptom ,business ,Sokal Score ,neoplasms ,medicine.drug - Abstract
Abstract 4494 Background: Although imatinib could induce efficacious and stable responses in patients with chronic myeloid leukemia (CML), resistance is increasingly problematic. Dasatinib, a BCR-ABL inhibitor with 325-fold greater potency in vitro than imatinib, induced MCyR 59%, CCyR 48%, PFS 90% and OS 96% for patients who can not tolerate or are resistant to imatinib in START-C. Method: We assessed retrospectively the efficacy and safety of dasatinib in patients with chronic phase (CP)-CML, resistant or intolerant to imatinib who received dasatinib 70 mg to 140 mg per day. Dose was adjusted according to toxicity. Result: Between 21 June 2005 and 31 March 2010, medical records of 47 patients from 6 centers in Korea were reviewed: 22 with imatinib-resistant and 1 with imatinib-intolerant CP-CML. 8 Imatinib–resistant ABL kinase domain mutations were found including E255K, T315I, F317L. Median duration of dasatinib therapy was 20.6 months. CHR, MCyR, CCyR and MMR was attained in 91%, 79%, 56% and 44% of patients, respectively. 18 month MMR rate was 71%, 67% in imatinib-intolerant and 53% in imatinib-resistant group. There was no difference in PFS according to the Sokal score, to the best response of imatinib to the type of mutation. 3-year PFS was 71% and OS was 79% with a median follow up of 20.6 months. There was no disease progression or death in imatinib intolerant group. Grade 3/4 anemia, neutropenia and thrombocytopenia were reported in 36%, 49% and 45% of patients, respectively. Non-hematologic toxicity (grade 3/4) consisted of infection(15%), dyspnea(4%), pleural effusion(6%), abdominal pain(2%) and skin rash(2%). Conclusion: Dasatinib showed promising efficacy and tolerability in imatinib-resistant or -intolerant CP-CML in Korean patients. Disclosures: No relevant conflicts of interest to declare.
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- 2010
43. Hematopoietic Cell Transplantation from an HLA-Mismatched Familial Donor After Reduced-Intensity Conditioning Containing Busulfan, Fludarabine, and Antithymocyte Globulin for Patients with Acute Leukemia and Myelodysplastic Syndrome
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Dae-Young Kim, Kyoo Hyung Lee, Jung-Hee Lee, Young-Ah Kang, Miee Seol, Young-Shin Lee, Mijin Jeon, and Je-Hwan Lee
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medicine.medical_specialty ,Acute leukemia ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Gastroenterology ,Surgery ,Fludarabine ,Transplantation ,Leukemia ,Blood cell depletion therapy ,hemic and lymphatic diseases ,Internal medicine ,Acute lymphocytic leukemia ,medicine ,business ,Busulfan ,medicine.drug - Abstract
Abstract 3538 For patients who suffer hematologic malignancies and lack suitable HLA-matched sibling or unrelated donors, there is a need to develop a safe and effective method of hematopoietic cell transplantation (HCT) from an HLA-mismatched family donor. In a previous report including 29 patients with acute leukemia and myelodysplastic syndrome (MDS), we showed that HCT from an HLA-mismatched familial donor is feasible without ex vivo-T cell depletion when reduced-intensity conditioning (RIC) with busulfan (BU), fludarabine (FLU), and antithymocyte globulin (ATG) is performed (Biol Blood Marrow Transplant 15: 61–72, 2009). Since the publication, we have extended our experience of HLA-mismatched HCT using same approach in 54 additional patients. Thus, the entire cohort of 83 patients, transplanted between April 2004 and December 2009, consisted of 47 male and 36 female with median age of 40 years (range, 16–70). Fifty-two patients had acute myelogenous leukemia (AML), 16 had acute lymphoblastic leukemia (ALL), and 15 had MDS. Of 68 patients with acute leukemia, 15 were in their 1st complete remission (CR) status, 19 in 2nd/3rd CR, and 34 in a refractory state. Twelve patients had undergone allogeneic HCT previously. RIC included iv BU 3.2 mg/kg/day ×2, FLU 30 mg/m2/day ×6, and ATG [Thymoglobulin 3 mg/kg/day ×4 (n=69) or ×3 (n=12); or Lymphoglobulin 15 mg/kg/day ×4 (n=2)]. Cell donors (age, 3–68 years) were either mother (n=24), HLA-haploidentical sibling (n=21), or offspring (n=38) of the patients with a mean HLA-antigen disparities of 2.24/6 in both graft-versus-host and rejection directions. Eleven of 71 evaluated donor-patient pairs (15%) showed natural killer (NK) cell-alloreactivity. The donors received granulocyte-colony stimulating factor (10 μg/kg/day) for 4 to 7 days and underwent daily 2 to 5 leukapheresis. Collected cells were infused into patients without further manipulation [medians (range) of; 8.1 (1.8-17.0)x108/kg mononuclear cells, 7.5 (0.2-73.5)x106/kg CD34+ cells, and 4.8 (0.5-10.0)x108/kg CD3+ cells]. Graft-versus-host disease (GVHD) prophylaxis included cyclosporine and methotrexate. As a part of separate phase 1/2 studies, 20 patients received donor-derived NK cells (up to 1×108/kg) after HCT. Other than 7 patients who had progressive leukemia or died early, all remaining 76 patients achieved absolute neutrophil count >500/μL median 13.5 days (range, 9–53; cumulative incidence, 92%). Seventy-two patients achieved platelet count >20,000/μL median 17 days (range, 11–119; cumulative incidence, 87%). Cumulative incidences for grade II-IV acute and chronic GVHD were 20% (95% CI, 13–30%) and 35% (95% CI, 26–47%), respectively. After median follow-up of 16.3 months (range, 6.3–72.9), 4 patients experienced secondary graft failure (cumulative incidence, 5%; 95% CI, 2–13%). Sixteen patients died without leukemia/MDS progression (4 due to acute GVHD, 3 secondary graft failure, 2 pulmonary complications, 1 EBV-PTLD, 1 EBV hepatitis, 1 CMV colitis, and 4 other infections), giving 1-year transplantation-related mortality (TRM) of 18% (95%, 11–28%). Thirty-five patients experienced leukemia/MDS progression. Cumulative incidences for disease progression were 21% for patients with acute leukemia in the 1st CR, 35% for acute leukemia in 2nd/3rd CR, 71% for refractory acute leukemia, and 20% for MDS. Kaplan-Meier event-free and overall survivals were 62% and 61% for patients with acute leukemia in 1st CR, 55% and 35% for acute leukemia in 2nd/3rd CR, 8% and 6% for refractory acute leukemia, and 53% and 50% for MDS, respectively. Disease status [standard risk (acute leukemia in CR and low-risk MDS) vs. high risk (refractory acute leukemia and high-risk MDS)] was an independent predictors for disease progression (P Disclosures: Lee: Genzyme: Honoraria; Otsuka Phamaceuticals: Consultancy.
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- 2010
44. Genetic Alterations of Wilms' Tumor 1 (WT1) Gene In Korean Patients with Normal Karyotype Acute Myeloid Leukemia
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Miee Seoul, Yunsuk Choi, Sung-Nam Lim, Je-Hwan Lee, Young-Shin Lee, Dae-Young Kim, Young-Ah Kang, Eun-Hye Hur, Sung-Doo Kim, Kyoo-Hyung Lee, Mijin Jeon, and Jung-Hee Lee
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medicine.medical_specialty ,Mutation ,Immunology ,Induction chemotherapy ,Single-nucleotide polymorphism ,Wilms' tumor ,Cell Biology ,Hematology ,Biology ,medicine.disease ,medicine.disease_cause ,Biochemistry ,Gastroenterology ,Leukemia ,Internal medicine ,Genotype ,Gene duplication ,medicine ,Cancer research ,SNP - Abstract
Abstract 4852 Introduction: Acquired mutations of the WT1 gene have been reported in 5–10% of normal karyotype AML (NK-AML) patients. Poor prognostic impact of the mutations has been reported, but some studied found no such correlation. Recent report from Germany showed the association of single nucleotide polymorphism (SNP) rs16754 status with clinical outcomes in NK-AML (J Clin Oncol 2009; 28:578). We assessed clinical implication of WT1 gene alterations in Korean patients with NK-AML. Patients and Methods: This study included a total of 75 patients with NK-AML. All patients received standard induction chemotherapy (‘7+3’ regimen) at the Asan Medical Center, Seoul, Korea between May 1999 and Dec 2006. WT1 exons 7 and 9 were amplified using polymerase chain reaction (PCR) and purified PCR fragments were directly sequenced. The clinico-laboratory data were retrieved from the AMC Leukemia Registry. Results: WT1 mutations were found in four patients (5.3%): two duplication mutations and two insertion mutations. All mutations were in exon 7 and none in exon 9. Two of four patients harboring WT1 mutation failed to achieve complete remission (CR) and died at 3.9 and 7.0 months after diagnosis of AML. One of two patients attaining CR was alive without relapse at 44.0 month and another died in CR at 4.7 months. WT1 SNP rs16754 was AA genotype (WT1AA) in 5 (3.7%), AG (WT1AG) in 29 (38.2%), and GG (WT1GG) in 41 (54.7%). The findings are significantly different from those of German report (WT1AA in 74.3%, WT1AG in 24.1%, and WT1GG in 1.6%) (P Conclusion: The prognostic impact of WT1 mutation in NK-AML could not be assessed in this study due to low number of patients harboring the mutation, but three of four patients died with relatively short survival duration, suggesting poor prognosis of the patients with WT1 mutation. The frequency of WT1 SNPs rs16754 in our patients was different from that of German report and survivals were not significantly different according to the SNP genotypes. Disclosures: No relevant conflicts of interest to declare.
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- 2010
45. Prognostic Factors on Survival After Hematopoietic Stem Cell Transplantation for Adult Over 40 Years In Aplastic Anemia
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Jung Hye Choi, Byung Soo Kim, Myung Soo Hyun, Sung-Soo Yoon, Young-Don Joo, Jae-Yong Kwak, Sung-Hyun Kim, Deog-Yeon Jo, Sang Kyun Sohn, Hawk Kim, Kyoo Hyung Lee, Jong Ho Won, Ho-Jin Shin, and Sung-Hwa Bae
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medicine.medical_specialty ,Univariate analysis ,Neutrophil Engraftment ,Platelet Engraftment ,business.industry ,medicine.medical_treatment ,Immunology ,CD34 ,Cell Biology ,Hematology ,Human leukocyte antigen ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Gastroenterology ,Surgery ,Internal medicine ,medicine ,Aplastic anemia ,Stem cell ,business - Abstract
Abstract 1315 Younger age is an important favorable prognostic factor to undergo HSCT in adult patients with AA, however what makes the poor survival in elderly patients is not well known. In this study we analyzed the age factor on HSCT in adult AA. A total 225 adult AA patients who had undergone HSCT were enrolled in this study. The age at the time of HSCT in 57 patients were over 40 yrs (elderly group) and 168 patients were less than 40 years (younger group). Adult over than 40 years had poor survival (5 year survival rate [5YSR] 55.1% vs. 76%; p=0.003) and this tendency maintained not only in MRD setting (5YSR 58.2 vs. 82.1%; p=0.003) but also in AD setting (4YSR 43.2% vs. 63.2%; p=0.109). We explored the prognostic factors of age over 40 years. Gender (p=0.642), prior IST (p=1.0), time from diagnosis to HSCT (p=0.348), donor type (p=0.479), HLA matching (p=0.311), ABO incompatibility (p=0.504), conditioning regimen (p=0.412), use of BM as stem cell source (p=0.456), infused CD34+ cells (p=0.478) were not different between elderly and younger groups. Compared with younger group, patients in elderly group had similar HSCT results in terms of engraft failure (p=0.848), neutrophil engraftment (p=1.0), platelet engraftment (p=0.104), SOS (p=0.591), aGvHD (p=0.445), cGvHD (p=0.105), grade of cGvHD (p=0.321), resolution of cGvHD (p=0.503) and relapse after HSCT (p=0.754). The causes of death had no statistical differences between 2 groups; infection (84.2% vs. 69.7%; p=0.328), engraft failure (5.3% vs. 21.2%; p=0.232), GvHD (20.0% vs. 18.2%; p=1.0). The more units of PC transfusion (p=0.061), more female to male matching (p=0.089), delayed time to ANC>500/μ(median 17 vs. 15 days; p=0.012) and delayed time to ANC>1000/μ(median 19 vs. 17 days; p=0.008) were noted in elderly group. Days for platelet engraftment were not different (p=0.485). Univariate analysis for survival in elderly group showed followings: gender (p=0.406); prior IST (p=0.104); donor type (p=0.475); HLA matching (p=0.052); female to male (p=0.857); ABO incompatibility (p=0.943); BM as a stem cell source (p=0.697); TBI as conditioning (p=0.467); ATG as conditioning (p=0.989); engraft failure (p=0.006); SOS (p=0.001); aGvHD (p=0.689); G3/4 aGvHD (p=0.024); cGvHD (p=0.545); extensive cGvHD (0.701). Mutivariate analysis revealed engraft failure (HR 2.839, 95% CI 1.012–7.967; p=0.047) and VOD (HR 5.972, 95% CI 1.597–22.331; p=0.008) were significant prognostic factors for survival. No prior IST, HLA full matching, successful engraftment, no SOS and no grade 3/4 aGvHD were the predictors of favorable survival in patients over 40 years old with AA. In conclusion, to prolong the HSCT survival for adult over 40 years in AA, HSCT without IST, full HLA matching, the prevention of engraft failure by using PB as a stem cell source and active management of SOS and effective GvHD prevention should be considered. Disclosures: No relevant conflicts of interest to declare.
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- 2010
46. Biologic Features and Clinical Outcomes According to Age Groups In Myelodysplastic Syndrome
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Yunsuk Choi, Sung-Nam Lim, Kyoo-Hyung Lee, Mijin Jeon, Young Hoon Park, Jung-Hee Lee, Dae-Young Kim, Young-Ah Kang, Miee Seol, Sung-Doo Kim, Je-Hwan Lee, Seungbum Lee, and Young-Shin Lee
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medicine.medical_specialty ,Chemotherapy ,business.industry ,Clinical study design ,medicine.medical_treatment ,Immunology ,ECOG Performance Status ,Cell Biology ,Hematology ,Disease ,Biochemistry ,Chemotherapy regimen ,Surgery ,Transplantation ,Age groups ,Internal medicine ,medicine ,Age stratification ,business - Abstract
Abstract 4963 Myelodysplastic syndrome (MDS) is a disease of the elderly, but can also affect younger people. Age is known to be an important prognostic factor in MDS but age variable is not included in most prognostic scoring systems because it is not thought as a disease-related variable. Many reports have showed that MDS is seen one to two decades earlier in Far Eastern countries than Western countries. We retrospectively investigated the differences in biologic features and clinical outcomes according to different age groups in Korean patients with MDS. Primary end points of our study were overall survival (OS) and progression-free survival (PFS). PFS was defined as time from diagnosis to AML progression or death. About one third of the patients received intensive treatment including chemotherapy, hypomethylating treatment or hematopoietic cell transplantation. Therefore, all survival data were censored at the start of intensive treatment to eliminate the influence of the treatments on clinical outcomes. A total of 403 patients, 248 males and 155 females, were included in this study. Median age was 54 years. We divided the patients into three age groups: ≤50 years (n=181), 51 to 60 (n=81), and over 60 (n=141). Baseline biologic features were significantly different according to three age groups: with increasing age, more male preponderance (P=0.009), more BM blast percentage (P60, P=0.011), poorer ECOG performance status (P=0.004), higher IPSS risk group (P=0.019). Five-year survival probabilities were significantly different according to age groups (≤ 50 vs. 51–60 vs. > 60; OS, 66.8% vs. 28.5% vs. 12.2%, P 60; OS, RR 2.3 (P=0.037) and RR 4.6 (P Conclusion: Biologic features and clinical outcomes were significantly different among age groups in MDS. Clinical outcomes were better in younger age group independently of biologic features. Survivals (OS & PFS) were better in younger age group and survival differences by age groups were observed in both lower and higher risk MDS, suggesting that age stratification should be considered in treatment decision and clinical trial design. Disclosures: No relevant conflicts of interest to declare.
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- 2010
47. Multicenter Retrospective Study on the Development of Peripheral Lymphocytosis During Second-Line Dasatinib Therapy for Chronic Myeloid Leukemia
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Je-Hwan Lee, Joon Seong Park, Dae-Young Kim, Sang Kyun Sohn, Jae-Yong Kwak, Ho-Young Yhim, Jun Ho Yi, Chul Won Jung, Hyeoung Joon Kim, Boram Ha, Yeo-Kyeoung Kim, Ha Yeon Lee, Won-Sik Lee, Su Jin Lee, Kyoo Hyung Lee, Inho Kim, Dong Hwan Kim, Seonyang Park, and Sung-Hyun Kim
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Oncology ,medicine.medical_specialty ,Lymphocytosis ,business.industry ,Lymphocyte ,Incidence (epidemiology) ,Immunology ,Myeloid leukemia ,Retrospective cohort study ,Cell Biology ,Hematology ,Biochemistry ,Dasatinib ,Imatinib mesylate ,medicine.anatomical_structure ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Cumulative incidence ,medicine.symptom ,business ,medicine.drug - Abstract
Abstract 2275 Background: Dasatinib is known to induce large granular lymphocyte (LGL) expansion, which correlates with better clinical efficacy. The current retrospective study attempted to investigate the incidence of lymphocytosis following second-line dasatinib therapy in chronic myeloid leukemia (CML) and to analyze the clinical factors predictive of the development of lymphocytosis, as well as association with treatment outcomes. Method: Fifty CML patients who failed imatinib treatment and received dasatinib for 3 months or more, were enrolled from 9 centers in the Republic of Korea. The cumulative incidence of lymphocytosis was assessed, and cytogenetic and molecular response, treatment failure, loss of response, progression to advanced disease, and survival were evaluated and analyzed according to the development of lymphocytosis. Results: After a median of 17 months of dasatinib therapy, complete cytogenetic (CCR) and major molecular response (MMR) was noted in 23 and 16 patients, respectively. Twenty three patients (46%) developed lymphocytosis following dasatinib therapy (median onset 4 months). No clinical predictive factor for the development of lymphocytosis was found. The cytogenetic response was significantly better in the group that developed lymphocytosis (LC+), as compared to the group without lymphocytosis (LC-); the LC+ group showed a higher complete cytogenetic response (CCyR; 78.3% vs. 29.6%, p=0.001) and major molecular response (MMR; 52.2% vs. 14.8%, p=0.005), in comparison to the LC- group. The development of lymphocytosis after dasatinib was identified as a favorable independent marker for predicting a CCyR (p=0.002) or MMR following dasatinib therapy (p=0.003). Conclusion: The present study suggested that 1) lymphocytosis following dasatinib therapy is not rare phenomenon with incidence of 46%; 2) it might be associated with higher response following dasatinib therapy. Further study is necessary to identify which subset of lymphocytes was expanded and to reveal the exact mechanism by which dasatinib induces lymphocyte expansion. Disclosures: No relevant conflicts of interest to declare.
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- 2010
48. A Multi-Center, Open Label Study Evaluating the Efficacy of Iron Chelation Therapy with Deferasirox In Transfusional Iron Overload Patients with Myelodysplastic Syndromes or Aplastic Anemia Using Quantitative R2 mri
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Yoo-Hong Min, Hyeoung Joon Kim, Kyoo-Hyung Lee, Jae Hoon Lee, Hee-Sook Park, Jin Seok Kim, Hyeok Shim, Chu-Myung Seung, Chul Soo Kim, Jooseop Chung, Myung Soo Hyun, Deog-Yeon Jo, Chul Won Jung, Sang Kyun Sohn, Hwi-Joong Yoon, Byung Soo Kim, Young-Don Joo, and Chi-Young Park
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Abstract 1125 Transfusion-related iron overload and its consequences are emerging challenges in chronically transfused patients with myelodysplastic syndromes (MDS) or aplastic anemia (AA). Measurement of liver iron concentration (LIC) is used as a surrogate for total iron burden to guide chelation therapy in transfusion-dependent patients. Although deferasirox (Exjade®, ICL670) is an oral iron chelation agent that is now widely available for the treatment of transfusional hemosiderosis, the clinical data on its specific benefits of iron chelation, including reduction of LIC, in transfusion-related iron overload patients with MDS or AA has been limited. We have prospectively investigated the efficacy of deferasirox for iron chelation by serial measurement of serum ferritin level and LIC, which is measured in vivo using quantitative tissue proton transverse relaxation rates (R2) magnetic resonance imaging (MRI), in transfusional iron overload patients with MDS or AA. Here we report the interim analysis data. A total of 97 patients with de novo MDS (n = 44) or idiopathic AA (n = 53) showing serum ferritin level over 1,000ng/ml were enrolled from 23 institutes. All patients were regularly transfused and received a mean of 28.6 red blood cells (RBC) units in the year prior to the start of the study. Among MDS cases, 3 (8.3%), 25 (69.4%), and 4 cases (11.1%) were categorized as IPSS low-risk, intermediate-1-risk, and intermediate-2-risk group, respectively. In AA cases, 34 (64.2%) were severe form. Mean value of serum ferritin level in enrolled patients was 3,482.6±436.7 ng/ml in MDS, and 3,904.4±399.2 ng/ml in AA at the time of deferasirox initiation. LIC value was measured using quantitative R2 MRI and FerriScan (Resonance Health, Australia) analysis. Mean value of LIC was 20.8 ± 3.5 mg Fe/g dry weight in MDS and 22.6 ± 2.2 mg Fe/g dry weight in AA. Linear regression analysis indicated a close correlation between serum ferritin level and LIC (r=0.55, p Disclosures: No relevant conflicts of interest to declare.
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- 2010
49. High Dose Dexamethasone Vs. Conventional Dose Prednisolone for Adults with Immune Thrombocytopenia: a Prospective Multicenter Phase III Trial
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Hyo Jung Kim, Je-Hwan Lee, Dae Young Zang, Hawk Kim, Hun-Mo Ryoo, Sung Hwa Bae, Min Kyoung Kim, Won Sik Lee, Kyoo Hyung Lee, Jung-Hee Lee, Jae Hoo Park, Young Don Joo, and Myung Soo Hyun
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myalgia ,medicine.medical_specialty ,Intention-to-treat analysis ,business.industry ,medicine.medical_treatment ,Immunology ,Splenectomy ,Cell Biology ,Hematology ,Biochemistry ,Gastroenterology ,law.invention ,Randomized controlled trial ,law ,Internal medicine ,Toxicity ,medicine ,Prednisolone ,medicine.symptom ,business ,Adverse effect ,Dexamethasone ,medicine.drug - Abstract
Abstract 3687 Background: Prednisolone at a dose of 1 mg/kg/day (PRD) for 2 to 4 weeks is administered as front-line therapy to most adult patients with immune thrombocytopenia (ITP) who need to be treated. Recent results from 2 large single arm studies suggest high dose dexamethasone (DEX) as first-line treatment may produce a high sustained response rate. Therefore, we conducted prospective randomized trial comparing DEX with PRD as initial treatment of adult patients with newly diagnosed ITP. Methods: We did a randomized multicentre trial based on a 1:1 design. We enrolled treatment-naïve patients, 16 years or older, with a diagnosis of ITP according to the practice guidelines of the American Society of Hematology and a platelet count of 30×109/L or less. Patients with ITP were randomly assigned to receive either DEX 40 mg/day on day 1–4 (If the platelet count dropped below 3×109/L within the first six months, another four-day course of DEX was given) or PRD 1mg/kg/day for 4 weeks. The primary object of this study was the sustained response (platelet count>30×109/L after 6 months) rate. Second objectives are response rate at 4 weeks, predictors of steroid response, and toxicity. This study is registered at http://clinicaltrials.gov as NCT00451594. Results: From September 2005 to December 2009, 151 adults with ITP were randomly assigned (76 patients in the DEX arm, 75 patients in the PRD arm). Overall demographics were balanced between arms; Median age 44 years old (DEX:PRD 44 years old:44 years old); 69.5% female (DEX:PRD 73.7%:65.3%); median initial platelet count 17×109/L (DEX:PRD 16×109/L:17×109/L). Of 151 enrolled patients, 117 patients (57 patients in the DEX arm, 60 patients in the PRD arm) were evaluable in terms of sustained response. Sustained response rate by intention-to-treat (ITT) and per protocol were 25.0% and 33.3% in the DEX arm, 36.0% and 45.0% in the PRD arm, respectively (p=0.33 by ITT). Eight patients in the DEX arm and 17 patients in the PRD arm had a sustained platelet counts more than100×109/L. Fifteen patients had a sustained response after a single course of DEX and 6 patients among them required no further treatment during two to four year follow up. Median time to relapse in patients who had a sustained response was 1320 days and 1140 days, respectively. The response rate at day 28 was 68.2% in the DEX arm and 81.2% in the PRD arm. Pre-treatment platelet count was higher in patients who achieved sustained response (responder vs. non-responder: 17.1±7.8×109/L vs. 15.9±8.9×109/L). Eleven patients in the DEX arm and 8 patients in the PRD arm received splenectomy. Both treatments were well tolerated. Three patients represented side effects that were severe enough to discontinue the treatment in the PRD arm, including pneumonia (1), hyperglycemia (1), and myalgia (1). Six patients receiving DEX and 5 patients receiving PRD had G3 or more hyperglycemia. Conclusion: One or two courses of DEX were not more effective than PRD in adults with ITP. However, 19.7% of adult ITP had a sustained response with a single course of DEX. Initial treatment with DEX could be useful for identifying patients who may not require prolonged steroid treatment. Disclosures: No relevant conflicts of interest to declare.
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- 2010
50. Differences In Clinical Characteristics and Prognostic Features Between Patients with Myelodysplastic Syndromes (MDS) From Korea, Japan, and Germany
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Je-Hwan Lee, Jung-Hee Lee, Kyoo Hyung Lee, Ulrich Germing, Akira Matsuda, Norbert Gattermann, Andrea Kuendgen, and Rainer Haas
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Cytopenia ,medicine.medical_specialty ,Univariate analysis ,Multivariate analysis ,business.industry ,Myelodysplastic syndromes ,Immunology ,Induction chemotherapy ,Cell Biology ,Hematology ,medicine.disease ,Blast Count ,Biochemistry ,Pancytopenia ,Internal medicine ,medicine ,Asian country ,business - Abstract
Abstract 1882 Evidence exists for differences between eastern and western type MDS. However, for the development of the IPSS Score, 6 of the participating study groups were European or US, while only one group originated from Japan. In order to find out more about the differences in MDS patients (pts) from separate ethnic groups we performed an analysis of 1048 pts from Dusseldorf, Germany (G), 242 pts from Seoul, Korea (K), and 143 pts from Saitama, Japan (J). Initially, we compared clinical characteristics. Then we evaluated the influence of important prognostic factors. For all pts included at least the parameters needed to determine the IPSS had to be available. For survival analyses pts who received induction chemotherapy or allogeneic transplantation were excluded. Median age was 66 yrs in Germany, 54 in Korea, and 68 in Japan. The distribution of gender, with a male preponderance, was comparable in all cohorts. Median blast count was To evaluate the relevance of different prognostic factors we first compared the whole cohorts of not intensively treated pts. Since the result was all factors analyzed were important in German while many were not in Asian pts we decided to look at a smaller subgroup of German pts to compare similar sizes. Pts were chosen by chance to avoid any kind of bias by matching. The results are presented in table 1. Already survival was very different in the 3 groups: 31 months (ms) (G) vs 43 ms (K) vs 157 ms (J). In univariate analysis in German pts variables with significant influence on survival were Hb, sex, age, LDH, platelets, blast count, KT, and IPSS, while in the Korean and Japanese pts the 3 different cytopenias and LDH had no influence on survival (except a borderline influence of Hb in Japanese pts). Very striking was the importance of gender in the 2 Asian countries. In both men lived for a median of only about 2 years, comparable to German pts, while women had a very long survival with median not reached. Regarding KT risk, the intermediate risk group had in the Asian countries a significantly longer survival than in Germany (nr vs 24 ms), possibly due to a high frequency of +8. The IPSS divided, again in both Asian countries, 2 different risk groups, but not 4. Multivariate analysis identified Hb, platelets, blasts, LDH, age, and KT as independent risk factors for German pts, compared to ANC, blast count, and age in Korean, and blast count plus KT in Japanese pts. It is established that survival of Asian MDS pts is longer than that of European, but it remains unclear why there is such a strong difference between Korean and Japanese pts although the former are younger and most other features are very comparable between the two. The most striking features of Asian MDS are the strong influence of gender, as well as the lesser importance of cytopenias compared to European pts. This, together with a slight difference in the survival according to KT, leads to an inferior separation of risk groups by the IPSS. The most important factor with equal relevance in all MDS pts remains blast count. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2010
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