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  • American Society of Hematology  (7)
  • Kim, Inho  (7)
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  • American Society of Hematology  (7)
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  • 1
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2272-2272
    Abstract: Abstract 2272 To test the correlation of trough plasma Imatinib Mesylate (IM) levels and pharmacogenomic variation with cytogenetic or molecular responses, we measured trough plasma IM levels and analyzed various genetic polymorphisms in newly diagnosed CML patients at 6 months of IM treatment and compared them with the likelihood of achieving cytogenetic complete response (CyCR) or major molecular response to standard dose of IM. Newly diagnosed 94 CML patients were prospectively enrolled in the current study. CyCR was achieved in 71 patients (75.5%). Eighty-four patients (89.4%) showed optimal response (CyCR + cytogenetic partial response CyPR) at 6 months. Trough plasma IM levels were highly variable ranging from 203 to 4980 ng/ml: mean (±SD) was 1392±78.8 ng/ml. Among 47 patients with trough plasma IM level of 〈 1320 ng/ml, 39 patients (83.0%) showed optimal response and 8 (17.0%) suboptimal response. Among 47 patients with trough plasma IM level of ≥1320 ng/ml, 45 patients (95.7%) showed optimal response and 2 (4.3%) suboptimal response (P=0.045). Trough plasma IM level was 1346.0±78.3 ng/ml for the group with non-hematologic toxicity of grade 0 or 1 and 1969.6±365.3 for the group with grade 2–4, which was statistically significant (p=0.038). The impact of single nucleotide polymorphisms (SNPs) in cytochrome P450 (CYP) genes (CYP2D6, CYP3A4, CYP3A5, CYP2C9, CYP2C19, CYP2B6, CYP2C8, CYP1A2) and transporter genes (hOCT1, hOCT2, hOCT3, ABCG2, ABCC2, SLCO1B1, ABCB1) potentially associated with IM trough level was also investigated. The AA genotype in CYP2C19*2 (681G 〉 A) was significantly associated with higher IM trough level than dominant genotype (p=0.021), whereas transporter genes did not show any significant results. The CC genotype of ABCG2 (421C 〉 A) gene was related with CCyR (OR 3.47, 95% CI 1.09–11.05; p=0.030). In conclusion, the incidence of optimal responses in newly diagnosed CML patients who had been treated with standard dose of IM for 6 months was significantly higher in the patient group with trough plasma IM level of ≥1320 ng/ml than the group with 〈 1320 ng/ml, and the trough level of IM was influenced by CYP2C19 genotype. Checking trough plasma IM level together with cytogenetic and molecular data at milestone timing may guide the clinicians to adopt dose escalation or 2nd tyrosine kinase inhibitors in CML patients showing suboptimal response or resistance to standard dose of IM. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 4298-4298
    Abstract: Abstract 4298 Background Increasing number of autologous or allogeneic HSCT in Korea in this decade resulted in increasing requirement for second allogeneic hematopoietic stem cell transplantation (HSCT) as a result of the recurrence of primary disease or graft failure. Since Dec 2008, second HSCT has been approved by Korean government to be covered by national health insurance reimbursement system. However, there is no available data on the transplant outcomes following second allogeneic HSCT in Korea. Accordingly, the current study attempted to analyze the outcome of second allogeneic HSCT retrospectively. Methods Transplant data were collected retrospectively from 8 transplant centers in Korea. Inclusion criteria are as follows. 1) Age equal or over 15 years old, 2) Hematologic malignancies excluding aplastic anemia, PRCA, PNH or solid tumor, 3) Patients who underwent second alloHSCT receiving cord blood transplantation (CBT). Results Sixty four pts were included with following diagnoses: AML (n=28), ALL (n=5), CML (n=3), lymphoma (n=22), myeloma (n=5), and others (n=1). The median age was 37 (range 16-65). The first transplantation had been performed with autologous (59.4%) or allogeneic (40.6%) donors. The donors for second HSCT were HLA-identical sibling 32(47%), unrelated 28(49%), or haploidentical donor 2(4%). Conditioning regimen included TBI-based myeloablative 6(9%), non TBI myeloablative 19(30%), or reduced intensity regimen 38(60%). With median 16 months of follow up (range, 3 to 93 months), 40 pts died of transplant related toxicity (n=28; 70%), recurrence of primary disease (n=9; 22.5%) or other (n=3; 7.5%). After second HSCT, 56% were in complete remission, 38% in partial remission, and 6% were refractory. The 1- and 2- year overall survival rate was 42% and 29%, respectively. Conclusion The patients received non TBI conditioning regimens were shown longer survival. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 1707-1707
    Abstract: Abstract 1707 Core binding factor AML including t(8;21) and inv(16) have been associated with a relatively favorable prognosis compared with patients with normal or adverse karyotypes, and treated similarly. However, both t(8;21) and inv(16) AML seem to differ with respect to several biologic features and several reports demonstrated inferior outcome of t(8;21) compared with inv(16). Advanced age, higher WBC or granulocytic count, as well as CD56 expression or granulocytic sarcoma have been reported as poor prognostic factors in t(8;21) patients. Higher bone marrow (BM) blasts, lower platelets, and non-white race in t(8;21) AML adversely affected the probability to achieve CR. The KIT mutation is associated with poor prognosis in AML1-ETO-positive AML. Five-year survival rate was only around 40% in patients with t(8;21) having poor prognostic factors. Several chemotherapeutic strategies have been reported, among which high-dose cytarabine (HDAC) is generally the most effective option for successful postremission therapy. Furthermore, none of the randomized studies disclosed an advantage of allogeneic SCT (alloSCT) in this group of patients, given the relatively high treatment-related death (TRD) rate. Patients with t(8;21) AML with unfavorable prognosis may benefit from intensive postremission therapy such as early hematopoietic SCT. We conducted a retrospective study to investigate whether postremission therapies impact on survival according to prognostic factors in 132 AML patients with t(8;21) achieving first CR. Univariate analyses of prognostic factors for survival were performed in the patients with t(8;21), as well as more limited population of chemotherapy (CTx) group according to postremission therapies. The BM cellularity was a single most important independent prognostic factor on survival when using BM cellularity cutoffs as 90%. The 5-year overall survival (OS) in patients with t(8;21) and CTx group were significantly lower at 49.7% and 44.3% in patients with ≥ 90% BM cellularity, compared with 81.4% and 81.9% in those with 〈 90% BM cellularity, respectively (P = 0.001 and 0.027, respectively). The only other prognostic factor that influenced OS in CTx group was WBC count with cutoffs as 9.1 × 109/L. High WBC count was trend towards poor OS in CTx group (P = 0.067). In multivariate analysis, BM cellularity appeared to be the only independent prognostic factor for OS in either AML patients with t(8;21) (P = 0.002) or CTx group (P = 0.055). Interestingly, we found positive correlation between BM cellularity and WBC count (P = 0.013), peripheral blood (PB) blast percentage (P = 0.001) and serum LDH level (P = 0.017) but not hemoglobin level and BM blast percentage in a linear regression model. And also, we confirmed negative correlation between BM cellularity and platelet count (P = 0.009). It is speculated that BM cellularity represents on poor prognostic factors including WBC and platelet counts, and PB blast percentage in patients with t(8;21). By combining dichotomized WBC count and BM cellularity in a univariate analysis for OS in CTx group, three risk groups could be established: low risk group, WBC count less than 9.1 × 109/L and BM cellularity less than 90%; intermediate risk group, WBC count ≥ 9.1 × 109/L and BM cellularity less than 90%; high risk group, BM cellularity ≥ 90%. In CTx group, 5-year OS was 81.9% in low risk group, 64.8% in intermediate group, and 32.1% in high risk group (P = 0.041). In alloSCT group, 5-year OS was 94.1% in low risk group, 29.1% in intermediate risk group, and 77.8% in high risk group (P = 0.042). In low risk group, 5-year OS was 81.9% in CTx group, 65.6% in autologous SCT (autoSCT) group, 94.1% in alloSCT group. In intermediate risk group, 5-year OS was 64.8% in CTx group, 29.1% in alloSCT group. In high risk group, 5-year OS was 32.1% in CTx group, 52.5% in autoSCT group, and 77.8% in alloSCT group. We found that BM cellularity was the most powerful independent prognostic factor in AML patients with t(8;21). The newly proposed model using BM cellularity and WBC count demonstrated a simple and valid measurement as main prognostic factor. We suggest a risk-adapted postremissin strategies based on this prognostic model for AML with t(8;21) such as low and intermediate risk patients receiving three cycles or more than three cycles of HDAC CTx and high risk patients undergoing SCT in first CR as postremission therapy. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    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
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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  • 5
    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
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 6
    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
    RVK:
    RVK:
    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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  • 7
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 1092-1092
    Abstract: High-dose cytarabine (HDAC)-based postremission therapy has been generally considered to be more beneficial than allogeneic stem cell transplantation (alloSCT) for AML patients with core binding factor (CBF). However, advancements in methods and supportive care in SCT over decades have led to gradual improvement in the treatment-related mortality rate after alloSCT. Therefore, it could be considered that alloSCT after the first CR in AML with CBF patients may show better results than HDAC chemotherapy alone compared with past. We conducted a retrospective study in 169 patients with CBF AML aged less than 60 years collected in 18 institutions in Korea between 1994 and 2006, with comparing alloSCT (n= 60), autoSCT (n= 31) and HDAC chemotherapy (n= 78) as postremission therapy during first remission. With a median follow-up of 46 months, the probability of disease-free survival (DFS) and overall survival (OS) rates at 5 years were 67.8% and 66.6%, retrospectively. AlloSCT (83.1% ± 5.2%) shows a significantly improved 5-year probability of DFS over autoSCT (59.9% ± 9.6%) or HDAC (60.8% ± 6.2%; p=0.048). There was no differences in 5-year probability of OS from complete remission (CR) between 3 treatment arms. In comparison of DFS and OS according to period of enrollment of patients, 4-year probability of DFS or OS of the three groups prior to 2003 was not different, nonetheless, after 2003, 4-year probability of DFS was better in the group underwent alloSCT in comparison with the group without performing it (86.8% vs 70.0%; p=0.035), and in the group underwent SCT (alloSCT plus autoSCT) in comparison with the group without performing it (89.0% vs 67.3%; p=0.047). 4-year probability of OS has a tendency to be improved slightly in the group underwent SCT than the group without performing it (89.0% vs 67.3%; p=0.08). In comparison with prior to 2003, cumulative treatment-related mortality and relapse risk of alloSCT after 2003 was decreased to 13.5% vs 6.7% and 26.2% vs 6.9%, respectively, and depending on the result, 4-year probability of DFS and OS of the alloSCT showed the improvement from 73.9% and 63.3% prior to 2003 to 93.1% and 90.0% after 2003, respectively. This study has the limitation of retrospective study, nonetheless, it could suggest the possibility that alloSCT as a postremission therapy in AML with CBF patients after the first CR may be appropriate if a HLA matched sibling donor were available.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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