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  • American Society of Hematology  (64)
  • 1
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    Phase II Multicenter Study of Busulfan-Fludarabine Conditioning Regimen for cord Blood transplantation in Pediatric Acute Myeloid Leukemia
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 1928-1928
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1928-1928
    Abstract: Abstract 1928 Introduction. Cord blood transplantation (CBT) has become an alternative transplantation for various diseases. CBT has comparable efficacy with unrelated transplantation, but higher transplantation related mortality (TRM) rate upto 50% in early results has been a major obstacle. To reduce TRM, we studied reduced toxicity myeloablative conditioning regimen with busulfan and fludarabine for CBT in pediatric acute myeloid leukemia (AML) patients. Patients and methods. This study was a phase II prospective multicenter clinical trial (NCT01274195) and 27 patients were enrolled who underwent CBT with upto 2 HLA mismatch cord blood. Conditioning regimen was composed of fludarabine (40 mg/m2 once daily iv on days -8 ∼ -3), busulfan (0.8 mg/kg every 6 hours iv on days -6 ∼ -3) and rabbit thymoglobulin (2.5 mg/kg once daily iv on days -8 ∼ -6). For GVHD prophylaxis, cyclosporine and MMF were used. Results. Nine patients received single unit cord blood, and 18 patients received double unit cord blood. Median dose of nucleated cells and CD34+ cells were 4.23×107/kg (0.5–16.4) and 2.58×105/kg (0.33–6.77), respectively. Primary graft failure developed in 5 patients, and secondary graft failure occurred in 1 patient. Acute and chronic GVHD occurred in 16 patients (59.3%) and 10 patients (37%), respectively. TRM developed in 5 patients (cumulative incidence 22.2%), which included chronic GVHD-associated complication (n=1), post-transplantation lymphoproliferative disease (n=2), pneumonia (n=2), and diastolic cardiomyopathy (n=1). Relapse incidence was 30.9%. The 5-year overall and event-free survival were 46.3% and 40.0%, respectively. Patients who received single unit cord blood showed survival rate of 44.4%, and those who received double unit cord blood showed survival rate of 50%. Univariate analysis revealed that low nucleated cell count (P=0.011), low CD34+ cell count (P=0.002) were independent prognostic factor for survival. Conclusion. Reduced intensity conditioning regimen containing fludarabine and iv busulfan showed lower TRM rate than previous studies with myeloablative conditioning regimens. However graft failure and relapse rate were not satisfactory, and further study for optimization of conditioning regimen is warranted. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.1928.1928
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 2
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    Efficacy of Nilotinib Versus High-Dose Imatinib in Early Chronic Phase CML Patients Who Have Suboptimal Molecular Responses to Standard-Dose Imatinib (RE-NICE Multicenter Study)
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 2765-2765
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 2765-2765
    Abstract: Abstract 2765 In CML, achievement of major molecular response (MMR) is a significant prognostic factor as it has been shown to be associated with longer duration of complete cytogenetic response (CCyR) and long-term progression-free survival. In IRIS study, patients who achieved both CCyR and MMR showed higher progression-free survival rates, compared to those who had CCyR without MMR. Higher doses of imatinib are expected to yield higher CCyR and MMR rates, compared to standard dose of imatinib, and second-generation tyrosine kinase inhibitor, nilotinib also produces high CCyR and MMR rates in patients with CP CML who are resistant to imatinib. In this prospective study, the efficacy of nilotinib and high-dose imatinib was investigated in suboptimal molecular responders who received standard-dose imatinib as first-line therapy. Early CP CML patients who have achieved CCyR but no MMR after at least 18 months and up to 24 months (≥ 18 to ≤ 24 months) on first-line imatinib therapy at a daily dose of 400 mg were enrolled in this clinical trial, and informed consents were obtained from all patients prior to participation. In nilotinib arm, patients received oral dose of 400 mg BID (800 mg/day), and patients received 800 mg/day administrated as 400 mg BID in imatinib dose-escalation arm. To assess the drug efficacy, cytogenetics and RQ-PCR analysis were performed at regular intervals, and baseline mutational analysis was conducted for every patient with subsequent mutational analyses performed in patients demonstrating either lack of response or disease progression. Primary endpoint is to evaluate the cumulative MMR rates by 12 months, and secondary endpoints are to evaluate the cumulative CMR rates and time to and duration of MMR and CMR during further 24 month follow-up. Progression-free survival and safety profiles will also be assessed as secondary endpoints. Patients showing lack of response (lack of complete hematologic response (CHR) at 6 months, increasing WBC, no major cytogenetic response (MCyR) at 24 months), loss of response (loss of CHR or MCyR) or severe intolerance to treatment were allowed to crossover to the alternative treatment arm. With a data cut-off date of 18 Jul 2011, a total of 30 patients were randomized into nilotinib arm (n =13) or imatinib arm (n = 17), and 6 patients have crossed-over to nilotinib arm due to lack of response. With a median follow-up of 11 months (range, 0.2–28 mos), all patients have maintained CCyR without progression to advanced disease, and progressive decrease in BCR-ABL transcript levels was observed in all patients. Cumulative MMR rates at 20 months were significantly higher in nilotinib arm compared to imatinib dose-escalation arm (59.00% vs. 27.40%, P = 0.047), and patients treated with nilotinib also showed faster molecular response rates, with 5 patients achieving MMR within 3 months of nilotinib therapy. At the last follow-up, 7/13 (53.85%) and 2/11 (18.18%) patients achieved MMR in nilotinib arm and in high-dose imatinib arm, respectively, with 1 patient in nilotinib arm achieving 4-log reduction of BCR-ABL transcripts. Although toxicity was observed more frequently in imatinib dose-escalation arm, all patients currently maintain the initial dose (except 1 patient who interrupted imatinib therapy due to neurosurgical operation), and based on the toxicity data, no additional or serious adverse events were developed except for pre-existing toxicities before randomization. These preliminary results demonstrate that early intervention using nilotinib or dose escalation of imatinib could be recommended in suboptimal molecular responders, with nilotinib being more preferable. Through further clinical investigation on a large patient population and longer period of observation, efficacy and safety of early intervention of suboptimal molecular response using nilotinib or dose escalation of imatinib will be assessed. Updated data with longer follow-up duration will be presented in the meeting. Disclosures: Woodman: Novartis: Employment, Equity Ownership. Szczudlo:Novartis: Employment, Equity Ownership. Kim:Novartis: Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.2765.2765
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
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  • 3
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    Pharmacokinetics of Fludarabine in Pediatric Hematopoietic Stem Cell Transplantation
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 2466-2466
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2466-2466
    Abstract: Introduction: Fludarabine is a purine-analog which is effective for leukemic cells with lower toxicity. Thus it has been preferred for preparative regimens of hematopoietic stem cell transplantation (HSCT) recently. However, the pharmacokinetics of fludarabine in pediatric HSCT has not been studied before. This prospective study investigated the pharmacokinetics of fludarabine in children undergoing allogeneic HSCT, and attempted to establish the fludarabine administration in pediatric patients. Patients and Methods: Forty-three pediatric patients undergoing HSCT were enrolled to the study. The median age was 11.8 years old (range 1.3–17.3), and there were 31 male and 12 female patients. Among the 43 patients, there were 15 acute lymphoblastic leukemia (34.9%), 12 acute myeloid leukemia (27.9%), 3 severe aplastic anemia (7.0%), 3 chronic granulomatous disease (7.0%), and 10 other diseases (23.3%). The preparative regimens included cyclophosphamide with fludarabine, busulfan with fludarabine, busulfan with fludarabine and etoposide, which was selected according to the disease and risk group. Fludarabine was administered as 40 mg/m2/day i.v. over 30 minutes for 5 to 6 days, and the pharmacokinetic study was carried out at the first and last dose. Blood samplings were taken before administration and 0.5, 1, 3, 5, 8hr after the end of infusion. Fludarabine concentration was analyzed by high performance liquid chromatography-tandem mass spectrometry. Results: Median (min-max) fludarabine area under the drug concentration-time curve extrapolated to infinity (AUC0-∞) of the first day of infusion was 4.64 (2.71-9.52) μg*h/mL, apparent clearance 10.9 (3.28-26.49) L/h, and Cmax 1,222 (668-1,732) ng/mL. The AUC0-∞ was lower than previously reported AUC0-∞ of the adult study, but the median Cmax was higher than the result of adult study. In this study, the range of AUC and Cmax were narrower than those of adult data. When the AUC0-8hr of day 1 and the steady state (day 5 or day 6) was compared, the fludarabine exposure at steady state was 1.21 fold higher than the first day. In this study, the overall survival was 75.8%, and event-free survival was 60.9%. When grouped by median fludarabine AUC level, the high AUC group and low AUC group showed no significant difference in overall survival or relapse-free survival. Also, there was no significant difference in cumulative incidence of relapse or treatment-related mortality (TRM) between two groups. Neurotoxicity was observed in 5 patients (11.6%) and pulmonary toxicity was observed in 19 patients (44%). These toxicities were not significantly related to the level of fludarabine AUC. Conclusion: In this study, the fludarabine AUC(0-∞) and Cmax was similar with adults, and the range was narrower. Thus fludarabine exposure is considered to be similar with adult, and the recommended dosing for adults can be applied to children. This is the first study to investigate the pharmacokinetics of fludarabine in pediatric HSCT. As fludarabine is being more widely adopted for the pediatric HSCT, this study could provide useful data for the treatment in pediatric patients. Acknowledgment: This research was supported by a grant (11172MFDS288) from Ministry of Food and Drug safety in 2011. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.2466.2466
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
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  • 4
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    Generation of Antigen-Specific Cytotoxic T Lymphocytes with Peripheral B Cells Activated By α-Galactosylceramide
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 3838-3838
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3838-3838
    Abstract: Dendritic cells (DCs) are well known as the most potent professional antigen presenting cells (APCs). Nonetheless, the use of these cells in immunotherapy has been limited due to the time consuming and laborious steps required to generate DCs from monocytes in vitro. Therefore, alternative APCs has drawn much attention because of their relative convenience in manipulation. In this study, the efficacy of B cells as APCs, as compared to DCs, in induction of cytotoxic T lymphocytes (CTLs) against cytomegalovirus (CMV)-specific antigens was evaluated. B cells were isolated by depletion of peripheral blood mononuclear cell (PBMCs) from healthy individuals with MACS system, loaded with α-galactosylceramide (α-GalCer) for inducing B cell activation, and nucleofected with CMV-antigen coding plasmid DNA, pCK-pp65-IRES-IE1. As other APCs, monocyte-derived DCs were induced with various cytokines (GM-CSF, IL-4, IL-1b, TNF-a), for 6 days and nucleofected with the same plasmid DNA. Ag-nucleofected B cells or DCs were cocultured with T cells for 14 days in vitro. The cells were harvested and subsequently immunoassayed. Proliferation of cells was more expanded by about 25~32% in CMV-CTLs induced by DCs compared to of B cells, but there was no significant difference in immunogenicity between CMV-CTLs induced with B cells and DCs. Compared to CMV-CTLs induced by DCs, the CTLs induced by α-GalCer-loaded B cells induced similar cytotoxicity against CMV antigen (Ag) in vitro. The CMV-CTLs by α-GalCer-loaded B cells recognized CMV antigen pp65 (median 88 SFC/105) and IE-1 (median 86 SFC/105) in donor 1, and CMV antigen pp65 (median 31 SFC/105) and IE-1 (median 37 SFC/105) in donor 2. Similarly, the CMV-CTLs by DCs recognized CMV antigen pp65 (median 133 SFC/105) and IE-1 (median 32 SFC/105) in donor 1, and CMV antigen pp65 (median 37 SFC/105) and IE-1 (median 43 SFC/105) in donor 2. Immunogenicities of both CTLs were similar not only on IFN-γ ELISPOT (Enzyme-linked immunospot) assay but also on cytotoxicity assay. The CMV-CTLs by α-GalCer-loaded B cells have killing activity against CMV antigen pp65 (100%, at E:T ratio 10:1) and IE1 (85%, at E:T ratio 10:1) in donor 1, and CMV antigen pp65 (69%, at E:T ratio 10:1) and IE1 (27%, at E:T ratio 10:1) in donor 2. Also, the CMV-CTLs by DCs show killing activity against CMV antigen pp65 (100%, at E:T ratio 10:1) and IE1 (42%, at E:T ratio 10:1) in donor 1, and CMV antigen pp65 (88%, at E:T ratio 10:1) and IE1 (64%, at E:T ratio 10:1) in donor 2. These observations suggest that α-GalCer-loaded B cells could be used in general as APCs instead of DCs. Using the B cells as APCs have several benefits such as cost-effectiveness, less time-consuming, and less laborious compared to when DCs are used. Furthermore, nucleofection technique might be useful in delivering antigen-coding DNA, not only for virus antigens but also for tumor antigens, directly into the nucleus. Our results demonstrate that α-GalCer-loaded B cells could be potent APCs in generating antigen-specific CTLs for cellular vaccines and adoptive immunotherapy. Acknowledgment: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2012R1A1A2008316) and we thank Ann M. Leen, Helen E. Heslop and Malcomn K. Brenner from Center for Cell and Gene Therapy, Baylor College of Medicine Center for their kind help. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.3838.3838
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 5
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    Nilotinib Versus High-Dose Imatinib in Early Chronic Phase CML Patients Who Have Suboptimal Molecular Responses to Standard-Dose Imatinib: Updated Data From RE-Nice Study
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 3775-3775
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3775-3775
    Abstract: Abstract 3775 Background. In chronic myeloid leukemia (CML), achievement of optimal responses by time point has improved long-term outcomes. In contrast, several clinical studies investigating the clinical implications of suboptimal response showed that patients with suboptimal responses tend to have poor long-term outcomes. In IRIS study, patients who achieved major molecular response (MMR) at 18 months had event-free survival (EFS) benefit, compared to those who achieved complete cytogenetic response (CCyR) without MMR. However, the best treatment for these patients is still not confirmed. By the previous studies, sustaining standard-dose of imatinib (IM) is expected to yield less than 20 percent of additive MMR. In this prospective study, we investigated whether switching to nilotinib (NIL) or high-dose IM may be more effective for patients with suboptimal molecular response to IM as first-line therapy. Methods. Early chronic phase (CP) CML patients who have achieved CCyR but no MMR after at least 18 months and up to 24 months (≤ 18 to ≥24 months) on first-line IM therapy at a daily dose of 400 mg were enrolled in this clinical trial, and informed consents were obtained from all patients. In NIL arm, patients received oral dose of 400 mg BID (800 mg/day) and in high-dose IM arm, patients received 800 mg/day administrated as 400 mg BID. Primary endpoint is to evaluate the cumulative MMR rates by 12 months, and secondary endpoints are to evaluate the cumulative MMR, MR4.0 and undetectable molecular residual disease (UMRD) rates during further 24 month follow-up. Safety profiles will also be assessed. Patients showing lack of response (lack of complete hematologic response (CHR) at 6 months, increasing WBC, no major cytogenetic response (MCyR) at 24 months), loss of response (loss of CHR or MCyR) or severe intolerance to treatment were allowed to crossover to the alternative treatment. Results. With a data cut-off date of 10 Jul 2012, a total of 43 patients were randomized into NIL arm (n = 22) or high-dose IM arm (n = 21). With a median follow-up of 15 months (range, 1–36), all patients have maintained CCyR without progression to advanced disease, and progressive decrease in BCR-ABL1 transcript levels was observed in all patients. Cumulative incidence (CI) of MMR by 12 months showed no significant difference between NIL arm and high-dose IM arm (37.8 ± 11.9% vs 34.8 ± 10.6%, P = 0.789). In NIL arm, 3 in 22 (14%) and 2 in 22 (9%) patients achieved MR4.0 and UMRD, respectively, and in high-dose IM arm, 1 in 21 (5%) patients achieved MR4.0. Overall, the patients treated with high-dose IM showed toxicities more frequently, such as fatigue, dyspnea and decreased phosphate. In addition, 10 patients in high-dose IM arm have cross-over to NIL treatment due to lack of response (n=9) and intolerance (n=1), and the median duration of NIL treatment was 14 months (range, 7–26 months). Among them, 5 (50%) patients have achieved MMR with a median NIL treatment duration of 12 months (range, 3–18). Conclusions. These results demonstrate that early switching to NIL or dose escalation of IM could be recommended, considering the results of standard dose of IM in suboptimal molecular responders. When the tolerability of treatment was considered for switching to NIL or high-dose IM, NIL may be preferred. Through further clinical investigation on a large patient population and longer period observation, the efficacy and safety of early intervention of suboptimal molecular response using NIL or dose escalation of IM will be needed. Updated data with longer follow-up duration will be presented in the meeting. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.3775.3775
    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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  • 6
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    Dynamics and Characteristics of BCR-ABL1 Multiple Mutations in Tyrosine Kinase Inhibitor Resistant CML
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 1677-1677
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1677-1677
    Abstract: Abstract 1677 Background: BCR-ABL1 kinase domain (KD) point mutation causes resistance to tyrosine kinase inhibitors (TKI) in CML patients through impaired binding of TKI to the target site. One of the characteristics of patients with BCR-ABL1 kinase domain point mutations is the fact that some patients have multiple mutations. However there have not been many studies showing that data about clinical relevance or dynamics of multiple mutation during CML treatment. Methods: Since 2002, 414 CML patients were screened for mutation analysis due to sign of resistance to TKI including imatinib, nilotinib, dasatinib, bosutinib, radotinib or ponatinib at Seoul St Mary's Hospital using direct sequencing and ASO-PCR. Among them, 31 patients showed multiple mutations. We analyzed serial samples from the 31 patients using subcloning and sequencing to investigate whether the multiple mutations are on same clone (defined as compound clone), separated clones (defined as multiple clone) or co-existent clones (defined as mixed clone) and characterize its clinical relevance and dynamics. Results: Status of the patients with multiple mutations is shown in Table 1. In order to investigate whether the multiple mutations are on same clone or on separated clone, we cloned serial samples from the 31 patients. Cloning of cDNA region corresponding to BCR-ABL1 KD into plasmid was performed and followed by transformation into competent cells, colony formation, plasmid preparation of 20 colonies from each sample, and then direct sequencing. Multiple mutations of 65% patients (20 out of 31) existed compound mutation which means the individual mutant types are located on the same BCR-ABL1 molecule. In addition of major mutation types which were detectable in direct sequencing analysis, all the patients showed to have minor types of mutations which were found only through BCR-ABL1 KD cloning and subsequent colony sequencing. To make sure that this minor mutation types were not caused by sequencing error, we also analyzed of 3 patients who showed TKI resistance, but had no BCR-ABL1 mutation. In addition, samples from 3 normal persons were analyzed with the same method. The frequency of appearance of the minor types of point mutation was reduced in the patient group who showed TKI resistance, but had no BCR-ABL1 mutation, and then dramatically decreased in the normal person group, indicating that BCR-ABL1 gene in patients with point mutation are relatively unstable. Among 20 patients with compound mutation, 9 patients were available for serial timepoint samples under same TKI therapy. In all nine patients (100%), portion of compound clone was increased as treatment went on. With a median follow-up 53.3 months (range, 0–113.2 months), of 31 patients with multiple mutation, 7 patients remained alive; 4 of 11 (36%) in the multiple clone group vs 3 of 20 (15%) in the mixed clone group (P = 0.066). Conclusion: Analysis of serial samples from a same patient provided evidence of dynamic change of portion of compound mutation. In most case, portion of the clone containing compound mutation was increased as treatment went on, indicating the clone harboring compound mutation can take survival advantage over TKI treatment in comparison of the clone containing individual type of mutation. In addition, some patients showed change in individual mutation type comprising multiple mutations as treatment went on. Patients with compound clone showed poor outcomes compared with multiple clone group in our cohort, further investigation on a large patient cohort will be needed. Updated data with longer follow-up duration will be presented in the meeting. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.1677.1677
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 7
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    Comparison of Sokal, Hasford and EUTOS Scores in Terms of Long-Term Treatment Outcome According to the Risks in Each Prognostic Model: A Single Center Data Analyzed in 255 Early Chronic Phase Chronic Myeloid Leukemia Patients Treated with Frontline Imatinib Mesylate.
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 2794-2794
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 2794-2794
    Abstract: Abstract 2794 Background The main difference of recently developed new prognostic classification, EUTOS score, from the conventionally used Sokal and Hasford scores is the simplicity of adopting only 2 clinical parameters, basophil counts and size of spleen, to discriminate high vs. low risks in chronic myeloid leukemia (CML). Concerns may rise from possible inter-observer gap when measuring the size of spleen. While there is currently controversial debate on its prognostic power, we present our single center results of comparing EUTOS score with other two scores. Patients and Methods Among 380 adult patients, consecutively registered as early chronic phase (CP) CML at Seoul St. Mary's Hospital (Jan. 2004 – Apr. 2010), who received imatinib (IM) as frontline therapy, 255 were evaluable for analysis: subjects were strictly limited to those with documented clinical parameters measured at very early time of diagnosis by a single doctor, before any cytoreduction therapies. The median age was 42 years (range, 19–77) with a slight male predominance (57%). Cytogenetic and molecular responses were calculated at specific time points and cumulative rates of response were compared according to risk scores. Event-free survival (EFS) was analyzed by time from start of IM to the time of events, defined by death from any cause, primary or secondary resistance to IM, progression to advanced phases, intolerance to IM and switch to second line tyrosine kinase inhibitor (TKI) or allografting. Response assessment followed current European Leukemia Net recommendation. Results Median time from diagnosis to IM start was 14 days (range, 1–183). After a median follow-up duration of 56.6 months (range, 13.0–102.2) in survivors, there were 10 deaths and 3 patients with disease progression to accelerated phase of blastic crisis. Sixty-four patients had switched IM to second TKI due to either IM resistance or intolerance. Overall comparisons are described in Table 1. Of 42 EUTOS high risk patients, only 25 high risk patients by Sokal and 15 by Hasford were included. Almost 90% of either low or intermediate (INT) risk patients by all risk models achieved complete cytogenetic response (CCyR) at 12 months after IM, whereas high risk groups had lower rates, especially in EUTOS high risk (57%, p = 〈 0.0001). Regarding major molecular response (MMR) at 18 months, significant differences were observed according to risk stratifications by Sokal and EUTOS, but not in Hasford risks, in which the same proportion of low and INT risks achieved MMR (48%, P = 0.308). This seemingly less prominent prognostic difference of low vs. INT groups of Sokal and Hasford scores were further demonstrated by insignificant difference between these groups in cumulative incidence (CI) of CCyR and MMR. All 3 high risk groups showed significantly lower incidence of both CCyR and MMR compared to low risk groups. INT risk groups by Sokal and Hasford models failed to show statistical significance in all three outcomes: CI of CCyR and MMR, and 5-year EFS. Of note, high risk stratified by EUTOS score demonstrated the least favorable outcomes with strongest p-values (Table 1). Conclusion By simply comparing the p-values, our data may implicate that high risk group discriminated by the EUTOS score is predicted with more unfavorable outcomes in achieving CCyR, MMR and survival after IM frontline therapy. Furthermore, the lack of statistically significant difference between outcomes of low and INT risk groups by conventional risk models may challenge the need for future classification of INT from low risk in this era of TKI. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.2794.2794
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 8
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    Comparison of Clinical Diagnosis for Hereditary Spherocytosis with Molecular Diagnosis By Multi-Gene Target Sequencing in Korea
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 1243-1243
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 1243-1243
    Abstract: Background: Hereditary spherocytosis (HS) is the most common cause of hereditary hemolytic anemia. Current tests used to diagnose HS focus on the detection of hemolysis or indirectly assess protein defects. Direct methods to detect protein defects are complicated and difficult to implement. Recent next-generation sequencing (NGS) methods enable large-scale gene mutation analyses to be used for such diagnoses. In this study, we investigated the patterns of genetic variation associated with HS among the patients diagnosed with HS clinically. Specifically, we analyzed mutations in red blood cell membrane protein-encoding genes (17 genes) in context with 5 genes for the differential diagnosis (thalassemia, congenital dyserythropoietic anemia, paroxysmal nocturnal hemoglobinuria) in Korean HS. Methods: In total, 60 patients diagnosed with HS were enrolled in this study. Targeted sequencing of 43 genes (17 membrane protein-encoding genes, 20 enzyme-encoding genes, and 6 additional candidate genes) was performed using the Illumina HiSeq platform and variants were called according to a data-processing pipeline. Results: Of the 60 patients, 50 (83%) had one or more significant variants in a membrane protein encoding genes. A total of 54 significant variants (8 previously reported and 46 novel) were detected in 6 membrane protein-encoding genes; SPTB, ANK1, SPTA1, SLC4A1, EPB41, and EPB42. The most variants (28/60 patients) were detected in SPTB. Interestingly, concurrent mutations of genes encoding enzymes (ALDOB, GAPDH, and GSR) were detected along with mutations of membrane encoding genes. One patient diagnosed with HS harbored mutation of G6PD without mutation of HS related genes. Additionally, UGT1A1 mutations were present in 5 patients. Positive rate of osmotic fragility test was 86% among patients with HS related gene mutations. Conclusion: These results clarify the molecular genetic analysis is required for the accurate diagnosis of HS. About 17% of patients who were clinically diagnosed as HS revealed discrepancy with molecular diagnosis. 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.V128.22.1243.1243
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 9
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    The Outcome of 129 Korean Children with Hemophagocytic Lymphohistiocytosis.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 3847-3847
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 3847-3847
    Abstract: Chemotherapy and immunotherapy based treatments improved survival of patients with hemophagocytic lymphohistiocytosis(HLH), but the outcome is still unsatisfactory. We analyzed the putative prognostic factors in a nationwide cohort of patients with HLH. Retrospective data recruitment for the patients diagnosed as HLH during the past 10-year period from 1996 to 2005 was carried out by the Histiocytosis Working Party of the Korean Society of Hematology. The HLH diagnostic criteria of the Histiocyte Society were strictly applied to confirm the eligibility of patients for this study. We analyzed the outcome of pediatric patients with HLH according to the age at diagnosis, sex, central nervous system(CNS) involvement, disease condition(familial or secondary), treatment modalities and disease state after 2 months of initial treatment. One hundred twenty nine patients from 19 centers fulfilled the diagnostic criteria(n=112) and/or had affected siblings together with some of the criteria(n=17). The male to female ratio was 0.95:1. The probability of 3 year overall survival(OS) in HLH patients was 41% with a median follow-up of 51 months. The 3 year OS in patients under 12 months of age at presentation(n=23) was 21.7%, and 44.3% in those over 12 months of age(n=106)(p=0.001). The 3 year OS in patients with CNS involvement(n=16) was 29.1%, and 44.4% in patients without CNS involvement(n=112)(p=0.01). The 3 year OS in patients with active state after 2 months of initial treatment(n=63) was 14.1% compared to 77.2% in those with inactive state(n=61)(p=0.0001). The 3 year OS in patients who received hematopoietic stem cell transplantation(HSCT)(n=17) was 82.3%, and 35.2% in patients treated with chemoimmunotherapy only(n=112)(p=0.03). Among the HSCT patients, complete remission was obtained in 14 patients except 3 other patients who died of infection and graft failure at early post-transplant period. The reasons for HSCT were active disease after chemoimmunotherapy(n=8), relapsed disease(n=5), and familial HLH(n=4). Other prognostic factors were not significantly correlated with outcome in our survey. The age and CNS involvement at diagnosis, disease state after 2 months of initial treatment were important prognostic factors which affected the outcome of HLH significantly in this cohort. This survey also demonstrated excellent outcome of familial or relapsed, persistent secondary HLH after HSCT compared to chemoimmunotherapy only.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.3847.3847
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
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    Final Report of “Korean Multicenter AML-2000 Trial”: Intention to Treat Analysis Based on Cytogenetics Risk
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 2975-2975
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 2975-2975
    Abstract: Cytogenetics is still being considered the most powerful single prognostic factor, which is useful to determine the types of post-remission therapy in AML, though various molecular markers are available for predicting the prognosis of AML patients. Most phase III studies have failed to demonstrate a clear advantage of allografting over chemotherapy in terms of overall survival because of significant risk of transplant-related mortality. Optimal post-remission therapies in terms of frequencies (number of treatment) or intensities are not decided yet. In this study, since 2000, we investigated that outcomes of post-remission therapies(high-dose cytarabine (HDAC) vs autologous stem cell transplantation (AutoSCT) vs allogeneic stem cell transplantation from sibling or unrelated donors (AlloSCT)) based on cytogenetic risk (GPG, Good prognosis group; IPG, Intermediate prognosis group; PPG, Poor prognosis group by MRC definition) on the AML patients who achieved complete remission after induction chemotherapy. The aims of this prospective intention to treat analysis was to compare the CR, recovery kinetics, DFS and OS in the different prognostic groups. Three plus seven (idarubicin 12mg/m2, D1–D3; cytarabine 100mg/m2, D1–D7) were given to de novo AML, secondary AML and therapy-related AML. Then, HDAC or AutoSCT was given after intermediate dose (8gm/m2) of cytarabine to the patients with GPG. Three times of post-remission therapy including HDAC, or AutoSCT followed by two times of post-remission therapy were given to IPG or PPG. If HLA-identical sibling was available, then AlloSCT underwent after 1st post-remission therapy. Since January, 2000, 506 patients(18 centers) were enrolled up to December, 2007. Among them, 92.3% was de novo AML, and GPG, IPG and PPG were, 23.1%, 62.1% and 14.8% respectively. Over all complete remission rate after 1st induction was 79.0% and CR rate in GPG, IPG, PPG were 92.0%, 81.0% and 43.9% respectively(P & lt;0.001) in 476 patients who were eligible to this study. In Good Prognosis Group (GPG), survivals were not different between different treatment groups (5 year LFS: HDAC 34.2%, AutoSCT 63.5%, AlloSCT 54.8%, p=0.270; 5 year OS: HDAC 54.5%, AutoSCT 62.5%, AlloSCT 53.3%, p=0.676). However, beneficial effect of AlloSCT in post-remission therapy therapy was observed by multivariate analysis in terms of LFS compared to HDAC (HR of relapse for HDAC 3.198 compared to AlloSCT, p=0.045). Outcomes of HDAC group were inferior in GPG in terms of OS and LFS compared to other studies. This results may be due to low cumulative dose of Ara C, because patients of HDAC group in GPG treated just 1 cycle of IDAC before HDAC therapy. In addition, in our cohort, majority (80%) of GPG have t(8;21), which are known as having inferior survival results, compared to inv(16) group. In Intermediate Prognosis Group (IPG), survivals were not different among different types of treatment (5 year LFS: HDAC 31.1%, AutoSCT 42.4%, AlloSCT 55.0%, p=0.131; 5 year OS: HDAC 39.2%, AutoSCT 42.5%, AlloSCT 46.5%, p=0.491). AlloSCT group showed a trend of being superior to other therapeutic modalities in terms of LFS (p=0.07). AutoSCT group showed a trend of being superior to other therapeutic modalities in OS by multivariate analysis (HR of death for AutoSCT 0.539 compared to AlloSCT, p=0.085). In Poor Prognosis Group (PPG), though data showed slightly beneficial effect of AlloSCT in AML therapy, however, there were no significant statistical differences on OS/LFS in 3 types of consolidation therapy modalities (4 year LFS: HDAC 48.3%, AutoSCT 0%, AlloSCT 39.1%, p=0.379; 4 year OS: HDAC 21.4%, AutoSCT 33.3%, AlloSCT 56.1%, p=0.638). Based on this trial, Allo- or Auto-SCT over HDAC may have beneficial effects in some subgroup with high risk and young age, among the patients with good and intermediate cytogenetic risk. In GPG, “sufficient cumulative dose” of Ara C seems to be necessary to have a good outcome. However, GPG seems to be heterogenous group in terms of biology having poor prognosis when one has additional CG abnormalities on top of t(8;21) or inv(16), which ones need to investigate further. While finding more effective anti-AML molecules/monoclonal Ab’s are necessary, good therapeutic rationales in terms of choosing AlloSCT vs AutoSCT vs HDAC should be established. Same time, identifying for better cellular and molecular prognostic factors over cytogenetics are still relevant for designing “effective therapies, but minimal toxicities”.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.2975.2975
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
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