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  • American Society of Hematology  (35)
  • 11
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    Perfect Engraftment after Fludarabine, Cyclophosphamide Plus Thymoglobulin Conditioning Regimen for Unrelated Transplantation in Severe Aplastic Anemia: Phase II Prospective Multi-Center Study in Korea
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 3003-3003
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 3003-3003
    Abstract: Anti-thymocyte globulin (ATG) has been used in severe aplastic anemia (SAA) as a part of the conditioning regimen. Among the many kinds of ATG preparations, thymoglobulin had been found to be more effective in preventing graft-versus-host disease (GVHD) and rejection of organ transplants. After the promising result of the pilot study (Bone Marrow Transplant. 2004. 34; 939), phase II prospective multi-center clinical trial was performed with fludarabine, cyclophosphamide plus thymoglobulin conditioning regimen to allow good engraftment in unrelated transplantation for SAA. Twenty-eight patients underwent bone marrow (N=15) or mobilized peripheral blood (N=13) transplantation with cyclophosphamide (50 mg/kg once daily i.v. on days −9, −8, −7 & −6), fludarabine (30 mg/m^2 once daily i.v. on days −5, −4, −3 & −2) and thymoglobulin (2.5 mg/kg once daily i.v. on days −3, −2 & −1) from HLA matched unrelated donors. GVHD prophylaxis regimen was composed of cyclosporine (or tacrolimus), methotrexate, with or without low dose thymoglobulin (1.25 mg/kg once daily i.v. on days 7, 9 and 11). The median infused cell dose of nucleated cells and CD34 positive cells were 6.8×10^8/kg (1.3– 39.9×10^8/kg) and 5.2×10^6/kg (1.2–27.0×10^6/kg), respectively. The median number of days required for ANC of more than 0.5×10^9/l and 1.0×10^9/l were 14 days (10–35 days) and 15 days (11–40 days), respectively. The spontaneous platelet recovery to more than 20×10^9/l required a median of 22 days (22–182 days). Donor type hematologic recovery (donor type chimerism more than 90%) was achieved in all patients. Fourteen patient developed grade II–IV acute GVHD. The event free survival (EFS) was 73% and all events were transplantation related mortality (TRM) which included coagulopathy (N=3), PTLD (N=2), pneumonia (N=1), and myocardiac infarction (N=1). The EFS of patients who received bone marrow (65%) was not different from that of patients who received mobilized peripheral blood (82%) (P=0.37), but the EFS of patients who received immunosuppressive therapy (IST) previously (55%) was lower than that of patients who didn’t receive IST (92%), significantly (P=0.04). Fludarabine, cyclophosphamide plus thymoglobulin conditioning allows for the promising result of very good engraftment, although serious events occurred in some patients. We are now planning to start new multicenter study to decrease TRM by reducing the dose of cyclophosphamide.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.3003.3003
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 12
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    Improved Outcome of Reduced Toxicity Fludarabine, Cyclophosphamide Plus Thymoglobulin Conditioning Regimen for Unrelated Donor Transplantation in Severe Aplastic Anemia: Comparison of Two Multicenter Prospective Studies
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 220-220
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 220-220
    Abstract: Abstract 220 Introduction: Hematopoietic stem cell transplantation (HSCT) is a curative therapeutic modality for severe aplastic anemia, but optimal conditioning regimen for the HSCT with an unrelated donor has not been defined yet. As the thymoglobulin had been found to be more effective among many kinds of anti-thymocyte globulins, and fludarabine based conditioning regimens without total body irradiation have been reported to be promising for transplantation from unrelated donors in SAA, combination of fludarabine, cyclophosphamide and thymoglobulin conditioning regimens had been tried to reduce GVHD and to allow good engraftment. Our previous phase II study (study 1) of fludarabine, cyclophosphamide plus thymoglobulin conditioning regimen resulted in successful engraftment (100%), but treatment-related mortality (TRM) occurred in 9 (32.1%) patients (NCT00737685, Biol Blood Marrow Transplant. 2010.16;1582). As cyclophosphamide is more toxic than fludarabine with similar effect, then we performed a new phase II study (study 2) with reduced toxicity fludarabine, cyclophosphamide plus thymoglobulin conditioning regimen by reducing dosage of cyclophosphamide and increasing dosage of fludarabine (NCT00882323). Patients and Methods: Twenty-eight and 31 patients were enrolled in study 1 and 2, respectively. In study 1, cyclophosphamide (50 mg/kg once daily i.v. on days −9, −8, −7 & −6), fludarabine (30 mg/m2̂ once daily i.v. on days −5, −4, −3 & −2) and thymoglobulin (2.5 mg/kg once daily i.v. on days −3, −2 & −1) were used for the conditioning regimen. For study 2, cyclophosphamide was reduced to 60 mg/kg once daily i.v. on days −8 & −7, and fludarabine was increased to 40 mg/m2̂ once daily i.v. on days −6, −5, −4, −3 & −2. Thymoglobulin (2.5 mg/kg once daily i.v. on days −4, −3 & −2) was also used. Results: Donor type hematologic recovery was achieved in all patients of study 1 (100%) and study 2 (100%). Events were occurred in 10 patients of study 1. Nine patients developed TRM, which included thrombotic microangiopathy (N=2), pneumonia (N=1), myocardiac infarction (N=1), post-transplantation lymphoprolifarative disease (N=3), and chronic GVHD-associated complications (N=2). Delayed graft failure occurred in 1 patient at 37 months after HSCT. In study 2, 2 patients had events. One patient developed TRM (pneumonia) and delayed graft failure occurred in 1 patient at 4 months after HSCT. Overall survival rate of study 2 (96.7%) was significantly higher than that of study 1 (67.9%) (P=0.005). Event free survival of patients was significantly better in study 2 (93.3%) compared to that of study 1 (64.3%) (P=0.014). Conclusions: Reduced toxicity fludarabine, cyclophosphamide plus thymoglobulin conditioning regimen showed promising results with same successful engraftment and less TRM compared to the previous combination and was optimal for the unrelated donor transplantation in severe aplastic anemia. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.220.220
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 13
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    Hereditary Hemolytic Anemia in Korea From 1997 to 2011: A Study by the Korean Hereditary Hemolytic Anemia Working Party of the Korean Society of Hematology
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 5157-5157
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 5157-5157
    Abstract: Abstract 5157 Background: With the development of diagnostic technique, an accurate diagnosis of hereditary hemolytic anemia (HHA)- red blood cell (RBC) membranopathy, hemoglobinopathy, RBC enzymopahty – have been made. Therefore, we surveyed the prevalence and characteristics of patients diagnosed as HHA during recent five years in Korea. Methods: Through the use of questionnaires, information on the clinical and laboratory findings of HHA diagnosed from 2007 to 2011 in Korea was collected. The globin gene analysis (direct sequencing) and RBC enzyme analysis was performed at the representative laboratories. A total of 203 cases were collected in this study by the Korean Hereditary Hemolytic Anemia Working Party of the Korean Society of Hematology. Results: Patients number of RBC membranopathy, hemoglobinopathy, and RBC enzymopahty was 125, 47, and 31, respectively. Percentage of patients with dominant family history was 57% in patients with hereditary spherocytosis (n=116) and dominant symptoms were anemia, jaundice, splenomegaly and gallstones. Osmotic fragility test and flow cytometric method for detection of RBC membrane defect were performed about 60% of patients. RBC membrane protein analysis using sodium dodecyl sulfate polyacrylamide gel electrophoresis was performed on 59 patients. Of the 47 cases of hemoglobinopathies, 36 cases (77%) were β-thalassemia minor, 10 cases (21%) were α-thalassemia minor and one case (2%) was unstable Hb, Hb M-Saskatoon (beta 64 His-→Tyr). Median age at diagnosis was 7 years (range: 6 months–58 years). Eleven of 47 cases (23%) had family history of HHA. As all thalassemia patients were thalassemia minor, they presented with mild jaundice or pallor. Of the 31 patients were diagnosed as RBC membranopathy, pyruvate kinase deficiency was 3 cases and glucose-6 phosphate dehydrogenase deficiency was 2, and other various forms were reported. Conclusions: We could confirm that accurate diagnosis has been made in more patients using elegant diagnostic technique. However, more defined diagnostic approaches were needed in this rare disease and further systematic supporting systems for patients and their families were warranted in public health aspect. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.5157.5157
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
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  • 14
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    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
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 3649-3649
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 3649-3649
    Abstract: 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 79 patients with de novo MDS (n = 29) or idiopathic AA (n = 50) showing serum ferritin level over 1,000ng/ml were enrolled from 23 institutes. All patients were regularly transfused and received a median of 30 red blood cells (RBC) units in the year prior to the start of the study. Among MDS cases, 3 (10.3%), 20 (69.0%), and 4 cases (13.8%) were categorized as IPSS low-risk, intermediate-1-risk, and intermediate-2-risk group, respectively. In AA cases, 34 (64%) were severe form. Mean value of serum ferritin level in enrolled patients was 4,417 ± 3,378 (4,788 ± 3,996 in MDS, 4,185 ± 2,962 in AA) ng/ml 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 23.9 ± 13.8 (26.1 ± 15.0 in MDS, 22.8 ± 13.2 in AA) mg Fe/g dry weight. Linear regression analysis indicated a close correlation between serum ferritin level and LIC (r=0.55, p 〈 0.001). Deferasirox was given orally at a dose of 20 mg/kg/day for at least 6 months to all patients. If the serum ferritin falls below 500 ng/ml, treatment was withheld. A consistent decrease in the serum ferritin level was demonstrated during the first 6 months in vast majority of patients despite of continued transfusion (209.7 ± 159.9 ng/ml and 324.0 ± 289.4 ng/ml per month in MDS and AA, respectively). Over the study period, patients with MDS or AA received a mean of 3.7 and 2.7 units RBC per month, respectively. After 6 months of medication, a slower decrease in the serum ferritin level was observed in MDS patients. In 30 cases, one-year medication of deferasirox was completed. At the end of study (EOS), the serum ferritin levels were significantly decreased to 3,085 ± 2,150 ng/ml (64.4% of baseline level) and 2,913 ± 2,232 ng/ml (69.6% of baseline level, p 〈 0.01) in MDS and AA, respectively. One-year follow-up R2 MRI could be evaluated in 24 cases, and LIC was significantly decreased to the level of 19.3 ± 13.6 mg Fe/g dry weight (67.4% of baseline value, p=0.01). Decrease in the level of LIC at EOS in MDS (64.3% of baseline) was comparable to that in AA cases (68.5% of baseline). The most common drug-related adverse events (AE) were gastrointestinal disturbances, non-progressive increase in serum creatinine, and skin rash. However, AE were transient and mild-to-moderate in severity. Deferasirox was discontinued in 28 (35.4%) cases because of death (7 in MDS and 6 in AA), patient refusal (11 cases), and decrease in the serum ferritin level below 500ng/ml (4 cases). All death was ascribed to disease-related causes including cytopenia in nine (11.4%) and disease progression in one (1.3%). This study clearly shows that deferasirox is effective in reducing LIC and serum ferritin level in transfusional iron overload patients with MDS or AA, even with ongoing transfusion requirement, and well tolerated. Careful assessment of patient’s transfusion requirement will be important in making dose adjustment according to purpose of iron chelation. Data from extension phase of this clinical trial may expand our knowledge about the beneficial effects of deferasirox on prolonging survival and improving quality of life in these patients.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.3649.3649
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 15
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    Clinical Features and Prognosis of MDS Patients with Chromosome 5 Abnormalities Other Than ‘5q-Syndrome’: Results of Multi-Center Analysis in Korea.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 4618-4618
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 4618-4618
    Abstract: Introduction: The myelodysplastic syndrome (MDS) is frequently associated with various chromosomal abnormalities. ‘5q− syndrome’ is low-risk MDS known as good responder of lenalidomide recently. However, the patients with other abnormalities in chromosome 5 showed quite different clinical features from those with ‘5q− syndrome’. The aim of this study was a retrospective evaluation for Korean MDS patients with abnormalities in chromosome 5 other than ‘5q− syndrome’. Materials and Methods: Among 456 patients with MDS diagnosed at 16 hospitals in Korea between 1996 and 2006, 370 with available cytogenetic data entered the study. Univariate and multivariate analysis were performed. Results: Ninety three patients (25.1%) showed abnormalities in chromosome 5 and the ‘5q− syndorme’ was only 10 patients (2.7%). Among the rest, 39 patients (10.5%) had various abnormalities other than 5q deletion such as translocation or 5 monosomy, 38 (10.3%) had complex abnormalities with 5q−, and 2 had mosaic pattern with normal chromosome. Four patients had isolated 5q− but blasts in marrow were over 5%. The deletion of 5q was interstitial but with a predominance for 5q13-33 deletions (34.8%). MDS patients with chromosome 5 abnormalities other than ‘5q− syndrome’ didn’t share the clinical features with ‘5q− syndrome’. There was no leukemic transformation in ‘5q− syndrome’ group, but 18 (21.7%) with other abnormalities in chromosome 5 finally transformed to acute leukemia. Five year overall survival was significantly inferior in non-’5q− syndrome’ patients than ‘5q− syndrome’ (14.3% vs. 79.6%, P=0.0115). Conclusions: Patients with isolated 5q− and excess blast ( 〉 5%), other abnormalities than isolated 5q−, or mosaic chromosome with isolated 5q− and normal chromosome didn’t share the clinical features such as lower rate of leukemic transformation and long survival.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.4618.4618
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 16
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    Incidence and Biologic Features of 5q Deletion and 5q- Syndrome in Myelodysplastic Syndrome in Korea; According to Reclassification of Myelodysplastic Syndrome by WHO 2008.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 2778-2778
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2778-2778
    Abstract: Abstract 2778 Poster Board II-754 Introduction: Interstitial deletions involving the long arm of chromosome 5, one of the good prognostic factors, are the most common chromosomal abnormality either as a sole or in combination with other abnormalities in myelodysplastic syndromes (MDS). However, the prognostic impact of del(5q) accompanied by additional chromosome abnormalities remains controversial. We investigated the hematologic, cytogenetic and prognostic features of del(5q) in MDS. Also, we mapped the deleted region on 5q by fluorescence in situ hybridization (FISH), whether the difference of deleted region between 5q- syndrome and MDS with del(5q) accompanied by additional abnormalities makes the clinical and prognostic differences. Methods: 137 adult patients, newly diagnosed as de novo MDS in Seoul National University Hospital from April 2000 through March 2009, were enrolled. We reclassified MDS subtypes according to WHO classification 2008. To compare the hematologic, cytogenetic and prognostic features according to presence of del(5q), we categorized the patients with del(5q) into 3 groups: patients with additional chromosomal abnormalities with del(5q) as 'MDS with del(5q)'; patients with other chromosomal abnormalities other than del(5q) as 'MDS with other chromosomal abnormalities (CA)'; and patients with isolated del(5q) as '5q- syndrome'. Also, the mapping with FISH for EGR1, CSF1R, and PDGFRβ on 5q, was performed in conjunction with G-banding to all patients and additional 16 patients with alleged del(5q) by G-banding from Korean MDS working party. Results: According to the new WHO classification of 2008, the 33 refractory anemia patients according to the previous WHO classification of 2001 were reclassified into refractory cytopenias with unilineage dysplasia (13 patients), refractory cytopenia with multilineage dysplasia (six patients) and MDS - unclassified (14 patients) (Fig 1). The median age of Korean MDS was 59 years, and the frequencies of 5q- syndrome and 5q deletion was 2.2% (3/137 patients) and 15.3%, respectively. Among 137 patients, 17 patients were grouped into 'MDS with del(5q)', and 53 patients into 'MDS with other CA'. The 'MDS with del(5q)' were significantly older and showed higher % of blasts in PB and BM than 'MDS with other CA'. And, they were categorized into higher risk group according to the International Prognostic Scoring System (IPSS) (Table 1). As a results of mapping for EGR1, PDGFRβ and CSF1R, deletion of all 3 regions was 93.3% in patients of 'MDS with del(5q)' and 66.7% in patients of '5q- syndrome', showing no difference in deleted genes between the two groups. Half (53%) of patients of 'MDS with del(5q)' accompanied complex abnormalities including chromosome 7 abnormalities. The del(5q) was detected only by FISH, showing discrepant results between G-banding and FISH analysis. Especially, marker chromosomes by G-banding in some patients were proved to be chromosome 5 with del(5q) by FISH. Conclusion: The biologic and prognostic features of MDS in Korea seem to be markedly different from those of Caucasian; younger age and low frequency of 5q- syndrome. The incidence of complex cytogenetic abnormalities including del(5q) was higher than that of Caucasian, while that of isolated del(5q) was quite low in Korea, which can explain that higher proportion of MDS with del(5q) belongs to higher risk IPSS group. And, we suggest FISH for del(5q) at initial diagnosis and during follow-up after treatment of MDS with alleged del(5q), since the presence of del(5q) in MDS is important for choosing the lenalidomide treatment. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.2778.2778
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 17
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    Efficacy of ICT with Deferasirox in Transfusional Iron Overloaded Patients with MDS or AA.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 3810-3810
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3810-3810
    Abstract: Abstract 3810 Poster Board III-746 PURPOSE Transfusion-related iron overload and its consequences are emerging challenges in chronically transfused patients with myelodysplastic syndromes (MDS) or aplastic anemia (AA). The clinical data on specific benefits of deferasirox in transfusion-related iron overload patients with MDS or AA has been limited. METHODS: We have prospectively investigated the efficacy of deferasirox by serial measurement of s-ferritin level and LIC by R2-MRI in transfusional iron overload patients with MDS or AA. RESULTS: A total of 79 patients with de novo MDS (n = 29) or idiopathic AA (n = 50) showing serum ferritin level over 1,000ng/ml were enrolled from 23 institutes. Mean value of s-ferritin level in enrolled patients was 4,788 ng/ml in MDS and 4,188 ng/ml in AA at the time of deferasirox initiation. Mean value of LIC was 24.4 mg Fe/g dry weight in MDS and 22.4 mg Fe/g dry weight in AA. Deferasirox was given orally at a dose of 20 mg/kg/day for at least 6 months to all patients and was withheld If the s-ferritin falls below 500 ng/ml. Over the study period, patients with MDS or AA received a mean of 3.7 and 2.7 units RBC per month, respectively. After 12 months of medication, s-ferritin level significantly decreased by 1824.0 ng/ml form baseline values, a reduction of 38.1% for patients with MDS (p 〈 0.0001) and significantly decreased by 3559.1 ng/ml (85.0%) for patients with AA (p 〈 0.0001). LIC decreased by 11.2 mg Fe/g dry weight, a reduction of 35.7% for patients with MDS, and significantly decreased by 8.1 mg Fe/g dry weight, a reduction of 27.6% for patients with AA (p=0.0028). The patients with lower transfusional requirements ( 〈 4 units/month) during the study showed significantly more reduction of LIC level than those with higher requirements (≥4 units/month) (35.7% vs. 2.8%; p 〈 0.0001). The most common drug-related adverse events (AE) were gastrointestinal disturbances and non-progressive increase in s-creatinine, however, AE were transient and mild-to-moderate in severity. All death was ascribed to disease-related causes including cytopenia in nine (11.4%) and disease progression in one (1.3%). CONCLUSION: Deferasirox is effective in reducing LIC and s-ferritin level in transfusional iron overload patients with MDS or AA, even with ongoing transfusion requirement, and well tolerated. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.3810.3810
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 18
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    Efficacy and Safety of Radotinib in Chronic Phase Chronic Myeloid Leukemia Patients with Resistance or Intolerance to BCR-ABL Tyrosine Kinase Inhibitors: Radotinib Phase 2 Clinical Trial
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 695-695
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 695-695
    Abstract: Abstract 695 Background Radotinib is a novel, selective Bcr-Abl tyrosine kinase inhibitor (TKI) developed by IL-YANG Pharm, South Korea. Radotinib showed a good efficacy and safety profile to chronic myeloid leukemia (CML) in preclinical and phase 1 clinical studies. To investigate the clinical efficacy and safety of radotinib 400 mg twice daily, data from CML patients treated during phase 2 clinical trial are reported. Methods Philadelphia chromosome (Ph+)-positive chronic phase CML (CP-CML) patients who failed or were intolerable to TKIs (imatinib and/or dasatinib and/or nilotinib) were enrolled between July 2009 and November 2011. Patients were treated with radotinib 400 mg twice daily for 12 cycles (1 cycle=4 weeks). The primary end point was an achievement of major cytogenetic response (MCyR, Ph+£35%) by 12 months. Safety parameters were also analyzed. Results A total of 77 CP CML patients (18 years of age or over) were enrolled from 12 sites in Korea, India, and Thailand. This analysis includes data from last enrolled patient who received at least 3 months of radotinib therapy. The median age of patients was 47 (range; 24–76) years, and 65 (84.4%) were imatinib-resistant and 12 (15.6%) were imatinib-intolerant. Four patients also had intolerance to dasatinib. With a median follow-up of 10.6 months, treatment with radotinib is ongoing in 46 patients (59.7%) and 31 patients (40.3%) discontinued the treatment including two deaths (2.6%). However, there were no CML-related deaths. Median duration of radotinib exposure was 296 (8–798) days. Overall MCyR rate was 63.6%, including 35 patients (45.4%) complete cytogenetic response and 14 patients (18.2%) partial cytogenetic response. The median time to MCyR was 2.8 months (85 days) and the median duration of MCyR was 315 (range; 5–726) days. Of patients achieving complete cytogenetic response, 37% (13/35) achieved major molecular response. Within follow-up durations, 44 patients (57.1%) required dose interruption and 41 patients (53.3%) had dose reduction. Most common grade 3/4 hematologic and laboratory adverse events (AEs) were thrombocytopenia (27.3%), neutropenia (10.4%), anemia (6.5%), and hyperbilirubinemia (31.2%). Common non-hematologic AEs were rash (29.8%), fatigue (14.3%), nausea/vomiting (14.3%), headache (13.0%), and pruritus (11.7%). The majority of AEs were easily manageable with temporal dose interruption and/or reductions. In all patients with CP-CML treated with second-line radotinib, estimated progression-free survival and overall survival rate at 12months was 84.9% (95% CI, 72.7–92.0%) and 97.4% (95% CI, 89.9–99.3% ), respectively. Conclusion Radotinib phase 2 trial confirmed the efficacy and safety of radotinib 400 mg twice daily in patients with CP-CML after failure to TKIs. Most of the AEs occurred in the early treatment period, were tolerable, and were easily controlled by dose interruption or reduction. Disclosures: Off Label Use: Radotinib, new BCR/ABL tyrosine kinase inhibitor, treatment for CML. Lee:IL-YANG Pharm.: Employment. Park:IL-YANG Pharm.: Employment. Woo:IL-YANG Pharm.: Employment. Kim:IL-YANG Pharm.: Employment. Lee:IL-YANG Pharm.: Employment. Cho:IL-YANG Pharm.: Employment. Shin:IL-YANG Pharm.: Employment. Kim:IL-YANG Pharm.: Employment. Kim:IL-YANG Pharm.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.695.695
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 19
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    The Clonal Origins of Leukemic Progression of Myelodysplasia
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 4307-4307
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 4307-4307
    Abstract: Introduction Acute myeloid leukemia (AML) that develops from pre-existing hematologic diseases, rather than developing de novo, is known as secondary AML (sAML). A number of hematologic malignancies can progress to sAML. However, the molecular and genetic characteristics behind the progression of hematologic malignancies to sAML remain unclear. To address this question and dissect the order of mutation acquisition throughout the course of the disease, we performed whole-exome sequencing and targeted deep sequencing on serial samples. Patients and Methods This study examined several cohorts with a combined total of 124 patients. This study was approved by research ethics boards at relevant institutions and samples were taken after informed consent. The discovery cohort (C1) consisted of 31 patients diagnosed with myelodysplasia who all progressed to sAML. Whole-exome sequencing (WXS) was performed for each case on bone marrow samples taken at the diagnosis of the antecedent malignancy and after sAML progression, as well as fractionated T-cell samples (CD3+). WXS (Agilent SureSelect v4) was performed on the 93 samples as per the manufacturer's protocol using an Illumina HiSeq 2000. The other cohorts included 72 non-progressed MDS patients (C2a, median follow-up of 3.5 years) and an additional 21 sAML patients (C2b) progressed to sAML from MDS, for whom samples from the MDS stage were not available. Targeted sequencing was performed using an Agilent custom probe set of the selected 92 genes. We multiplexed and sequenced the samples using an Illumina Hiseq 2000. Targeted deep sequencing was performed on all cohorts. Genomon-ITD was used to detect FLT3-ITD. Results The mean read depth retrieved for target regions for WXS data was 73x. After calling and prioritizing variants, we found a mean and median of 7.7 and 6 significant variants per patient at the time of initial diagnosis, and 12.4 and 10 variants after sAML progression, respectively. We also detected that FLT3-ITD emerged in 2 patients after sAML progression. The presence of variants in T-cell samples in 5 C1 and 20 C2a patients provides evidence on the relative timing of early events for a subset of patients. Both cohorts notably lack activated signaling pathway variants at this stage (Figure A). The T-cell variants in 5 C1 patients with pathway associations were all in genes involved in DNA methylation (DNMT3A, IDH1/2, and TET2) or splicing machinery (SRSF2 and SF3B1). This pattern was verified in 20 C2a patients except for a single case that had an NRAS-G13D mutation. These patients showed evidence of having clonal hematopoiesis. At MDS, there were a significant number of cases with variants in genes involved in DNA methylation and/or splicing machinery (35.5% and 48.3%, respectively). However, the portion of cases with variants affecting these pathways increased significantly at the MDS stage, but did not change much by the sAML stage (Figure C-D). On the other hand, variants in genes involved in activated signaling pathways showed a distinctive pattern. The portion of cases with variants affecting activated signaling pathways noticeably increased at the sAML step (25.8% to 54.8%) (Figure B). The changes in VAF between stages within cases of these variants revealed a similar pattern. In summary, clonal evolution patterns can be postulated based on the acquisition/expansion of mutations related to the three signature pathways (Figure E). Forty-eight percent of patients showed growth or development of clones containing activated signaling pathway variants at the sAML stage. Sixteen percent of patients developed the MDS from preleukemic mutations associated with DNA methylation or splicing machinery, and 26% first developed clones of this category at the MDS stage (a total of 42%). Conclusion Mutations in DNA methylation and splicing machinery genes are early disease events, expanding at the MDS stage but not during progression. On the other hand, activated signaling pathway mutations expand during progression, demonstrating that distinct categories of genetic lesions play roles at different stages of sAML in a generally fixed order. Figure Figure. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.4307.4307
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
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  • 20
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    Molecular Predictive Markers in Dose Escalation Treatment for Suboptimal Responders to Standard Dose Imatinib in CML
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 3221-3221
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 3221-3221
    Abstract: Introduction Imatinib mesylate (IMT) dose escalation has been proposed as a therapeutic option in patients (Pts) with chronic myeloid leukemia (CML) who failed to achieve optimal response with standard dose IMT. We report the results of prospective multi-center single arm phase ¥≥study evaluating efficacy of escalated dose IMT. We intended to identify patterns of molecular change using serial quantitative RT-PCR and its relationship with clinical outcome. We also planned to find predictive markers for outcome with array comparative genomic hybridization (aCGH) and epigenetic study of bcr gene in addition to BCR/ABL mutation. Patient and methods Pts in chronic phase (CP) CML who failed to achieve optimal response by European LeukemiaNET with adequate organ function were enrolled. Pts in accelerated phase (AP) or blast crisis (BC) who failed to achieve complete hematologic response after 3 months of IMT were also eligible. CP Pts received 600mg daily, while Pts in AP or BC received 600 or 800mg IMT daily. Pts received IMT for at least 12 months or until the appearance of a progressive disease, intolerable toxicity. Along with cytogenetic response (CyR), molecular response (MR) was assessed with BCR-ABL/ABL gene ratio of peripheral blood or bone marrow aspirate. Baseline BCR/ABL gene mutation test was performed using Matrix-assisted laser desorption/ionization time of flight mass spectrometry. Genome-wide screening for regions of genetic gains and losses with baseline blood samples was performed for 38 Pts using aCGH. Methylation status of 4 CpG sites in bcr gene promoter region was tested for 40 Pts and average methylation level was used for analysis. Blood samples at baseline and 6 months after dose escalation were tested. 29 optimal responders to standard dose IMT and 38 healthy donors were also tested for bcr methylation status for additional comparison. Results 71 Pts (median age 49.0 years, M:F=50:21) received escalated dose IMT. Median time to treatment failure (TTTFx) was 18.0 months and toxicities were manageable. 44 and 52 Pts were evaluable for FISH at 6 months and 1 year, where 16 and 17 Pts showed complete CyR (CCyR) respectively. For 61 Pts with serial MR data, TTTFx was longer in Pts who achieved molecular reduction of more than 50% within 6 months (Molecular early responder: MER) than who didn’t (p & lt;0.001). MER’s achieved CCyR more frequently at 6 months and 12 months (p=0.010, & lt;0.001 respectively). Of 24 Pts who had mutational status data, 4 had mutation. They experienced TFx within 12 months and all failed to achieve CCyR. aCGH revealed significant copy number (CN) gain in chromosome 16p11.2 in MER’s compared to non-MER’s (p=0.034). Tendency for increased CN in 22q11.23 and decreased CN in 17q12 was observed in MER’s without reaching statistical significance (p=0.072 and 0.070 respectively). 4 candidate genes within the above regions – GSTT1, SULTA1A, PYCARD, TADAZL – were evaluated for CN variation. GSTT1 CN loss was more frequently observed in MER’s (p=0.035). GSTT1 CN loss also predicted the longer TTTFx without reaching statistical significance (p=0.086). In epigenetic study, Pts in PCyR at the time of study enrollment had increased baseline bcr methylation compared to Pts in less than PCyR (p & lt;0.001). Pts who had increased amount of bcr methylation at 6 months compared to baseline had longer TTTFx compared to who did not (p=0.012). Baseline bcr methylation amount of study Pts was lower when compared to that of optimal responders and healthy donors (p=0.001 and p & lt;0.001 respectively). bcr methylation decreased with increased duration of standard dose IMT both in study Pts and optimal responders (p=0.042 and 0.004 respectively), although the pattern of decrease was different between the two groups (p & lt;0.001). In multivariate analysis baseline bcr methylation status was the only variable related to TTTFx (p=0.047). Conclusion Escalated dose IMT is a reasonable option for CML Pts showing less than optimal response to standard IMT. MER after escalated dose IMT is a useful early predictive marker for long term response. Mutational status of BCR-ABL at baseline is possibly important for response. Chromosome 16p11.2, 22q11.23 and 17q12 are potential locations related to IMT response and GSTT1 CN loss may be a genetic change affecting clinical outcome. bcr methylation status is an epigenetic marker associated with IMT response, where decreased bcr methylation status is related to poor IMT response.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.3221.3221
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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