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  • 1
    In: Blood, American Society of Hematology, Vol. 126, No. 6 ( 2015-08-06), p. 746-756
    Abstract: Nilotinib plus multiagent chemotherapy was feasible and showed a comparable outcome to previous results with imatinib for Ph-pos ALL. The achievement of deep MR with nilotinib at postremission correlated well with the clinical outcomes for Ph-pos ALL.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
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  • 2
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 55-55
    Abstract: We previously reported the interim analysis on the clinical outcome of nilotinib (Tasigna®, Novartis Pharma, Basel, Switzerland), when combined with multi-agent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) in adults. Herein, we reported the final results of the multicenter prospective phase2 trial of Adult Acute Lymphoblastic Leukemia Working Party, the Korean Society of Hematology. Newly diagnosed Ph+ALL patients aged 18 years old or more were eligible when they had adequate organ function. Diagnosis of Ph+ALL was performed via confirmation of the presence of Ph chromosome by conventional GTL-band technique, and/or positive molecular analysis with nested RT PCR for detection of BCR-ABL fusion transcripts. Written informed consent was obtained from all subjects. All patients received induction treatment consisting of vincristine, daunorubicin, oral or parenteral prednisolone, and nilotinib. After achieving complete remission (CR), subjects received either 5 courses of consolidation followed by 2-year maintenance with nilotinib, or allogeneic hematopoietic cell transplantation (alloHCT) depending on the donor availability, his/her tolerability, and patient’s wish. Nilotinib was administered twice a day with a single dose of 400mg (800mg per day) from day8 of induction until the initiation of conditioning for alloHCT or the end of maintenance therapy. Minimal residual disease (MRD) monitoring was performed at the central lab with quantitative RT-PCR assays for peripheral blood BCR-ABL RNA using LightCycler® Technology in serial; at the time of diagnosis, at hematologic CR(HCR), and every 3 months thereafter. BCR-ABL quantification was expressed relative to the amount of glucose-6-phosphate dehydrogenase (G6PDH) mRNA. The molecular response was defined as complete (MCR, MRD-negative) if the BCR-ABL/G6PDH ratio was less than 1x10-6. Toxicity was graded according to National Cancer Institute Common Toxicity Criteria (version 2.0). Subjects had been followed up for 2 years after alloHCT or during maintenance therapy. Data were frozen up in June, 2013. A total of 91 subjects (male: female = 45: 46) were enrolled onto the study between January 2009 and May 2012. The median age was 47 (range 18-71) years old. Type of BCR breakpoint was minor (e1a2) in 71% of patients. The median BCR-ABL/G6PDH ratio was 6.09 (bone marrow) and 3.28 (peripheral blood) at diagnosis. During induction, all subjects required blood product transfusion, and incidence of nonhematologic adverse events (AE) over grade 3 was 17% (jaundice), 18% (ALT elevation), 13% (lipase elevation), and 2% (pancreatitis). Neither QTc prolongation over 500ms nor significant arrhythmia happened among any subject and any cycle. HCR rate was 90% and median time to HCR was 27 days (range, 13-72); most of failure was due to death in aplasia (n=8). MCR rate at HCR was 55%, Cumulative MCR rate was 84%, and median time to MCR was 1.1 months (range, 0.6-15.8). Most common cause of dropout from study was treatment-related death (n=22; during induction/consolidation vs. after alloHCT = 12 vs. 10), and HREL (n=15). Nilotinib was interrupted 75 times among 64 subjects, reduced 14 times among 12 subjects, and discontinued permanently due to hematologic relapse (HREL, n=14), AE (n=6, over gr3:3), and other cause (n=2). Fifty nine patients underwent alloHCT, 34 with myeloablative and 25 with reduced-intensity conditioning. Incidences of acute graft-versus-host disease (GVHD) and chronic GVHD were 41% and 29%, respectively. With a median follow-up of 20.7 months of surviving subjects, estimated hematologic relapse-free survival (RFS), and overall survival (OS) rate at 2 years were 74% and 70%, respectively. Among subject achieving MCR, 2-year molecular RFS rate was 56%. When events were defined as ‘dropout due to AE, isolated molecular / extramedullary relapse, HREL, and death from any cause’, median event-free survival was 12.5 months. In this prospective study, nilotinib was shown to be effective for adult Ph+ALL, and concurrent administration of nilotinib with cytotoxic drug was well-tolerable, although death in aplasia during induction was the most common cause of failure of achieving HCR. In terms of MRD, potential of nilotinib to achieve and maintain MRD negativity were satisfactory (Clinicaltrials.gov NCT00844298). Disclosures: Off Label Use: Nilotinib for Ph+ALL-sientific and academic purpose.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1517-1517
    Abstract: Abstract 1517 Background: Incorporation of imatinib into classical cytotoxic chemotherapy has improved the response and survival of patients with Philadelphia chromosome-positive (Ph+) adult acute lymphoblastic leukemia (ALL). Nilotinib (Tasigna, Novartis Pharma, Basel, Switzerland), a second-generation tyrosine kinase inhibitor with enhanced in-vitro inhibition of BCR-ABL kinase, showed faster and deeper responses than imatinib among patients with chronic myeloid leukemia. Moreover, less serious gastrointestinal adverse effects of nilotinib may be beneficial to combination with intensive chemotherapy in Ph+ ALL when compared with imatinib. Herein, we report interim results of a prospective single-arm multicenter phase-2 study evaluating the safety and efficacy of nilotinib-combined multi-agent chemotherapy in Ph+ ALL. Methods: Patients aged over 18 years old were eligible if they had newly diagnosed Ph+ ALL, and adequate hepatic/renal/cardiac function. Diagnosis of Ph+ ALL was dependent upon confirmation of t(9;22) with cytogenetics by conventional GTL-band technique, and/or positive molecular analysis with nested RT PCR for detection of BCR-ABL fusion transcripts. Written informed consent was obtained from all patients. All patients received induction treatment consisting of vincristine, daunorubicin, oral prednisolone, and nilotinib. After achieving complete remission (CR), patients received either 5 courses of consolidation followed by 2-year maintenance with 6-mercaptopurine plus methotrexate, or allogeneic hematopoietic cell transplantation (alloHCT) according to the donor availability and his/her general condition. Nilotinib was administered twice a day with a single dose of 400mg (800mg per day) from day8 of induction until the initiation of alloHCT or the end of maintenance therapy. Quantitative RT-PCR assays were performed at the central lab with Light-Cycler Technology at the time of diagnosis, at CR, and every 3 months thereafter. BCR-ABL quantification was expressed relative to the amount of glucose-6-phosphate dehydrogenase (G6PDH) mRNA. The molecular response was defined as complete (MCR) if the BCR-ABL/G6PDH ratio was less than 1×10−6. Toxicity was graded according to National Cancer Institute Common Toxicity Criteria (version 2.0). For interim analysis, outcome was updated as of July 1, 2011. Results: A total of 50 consecutive patients (male: female = 22: 28) were enrolled onto the study between January 2009 and December 2010. The median age was 44.5 (range 18–71) years old. Type of BCR breakpoint was minor (e1a2) in 66% of patients. The median BCR-ABL/G6PDH ratio was 6.09 (bone marrow) and 3.08 (peripheral blood) at the diagnosis. Except five patients who died in aplasia during induction, 45 (90%) patients achieved hematologic remission (HCR), and MCR rate was 54% at the time of HCR. During the whole treatment periods, administration of nilotinib was interrupted 50 times among 30 patients, and dose was reduced among 6 ones. Of 45 patients who achieved HCR, median dose intensity (DI) of nilotinib between day8 and day of confirmation of HCR was 769.2mg (range 160–800), and MCR rates were not different among two subgroups when dichotomized using the median dose intensity (60.9% vs. 59.1%). During the induction, 20% of patients experienced ≥grade 3 jaundice, which were all reversible, and 2% experienced pancreatitis. Thirty three patients underwent alloHCT, 19 with myeloablative and 14 with non-myeloablative conditioning. Incidences of ≥grade 3 acute graft-versus-host disease (GVHD) and extensive chronic GVHD were 9% and 3%, respectively. With a median follow-up of 17.4 months (range, 6.9–29.1), estimated relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS) at 2 years were 71.1%, 49.4%, and 66.2%, respectively. Of 33 patients who underwent alloHCT, 2-year RFS, EFS, and OS rate were 70.5%, 60.0%, and 83.2%, respectively. Achievement of MCR and DI of nilotinib were not associated with outcome. Conclusion: Nilotinib was tolerable in combination with intensive chemotherapy for adult patients with Ph+ ALL, and the outcomes were comparable to previous results based on imatinib combination. Patient recruitment is ongoing currently based on this interim analysis, and the final results are expected in 2014. Disclosures: Off Label Use: Nilotinib is used as 'off-label drug' for Philadelphia chromosome-positive acute lymphoblastic leukemia in this trial. We have achieved the permission for the use of this drug in this clinical trial from the Korean FDA.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
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  • 4
    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
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 5
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3536-3536
    Abstract: Abstract 3536 Prognosis of patients with NHL who underwent relapse or progression after autoSCT is generally dismal and treatment option is limited. AlloSCT has been performed to overcome this problem and long term survivors have been reported. However, substantial transplant-related mortality (TRM) is a significant problem. We report clinical outcomes of alloSCT in these patients and DLI after failure of alloSCT along with analysis of risk factors for treatment results and adverse events. This retrospective study was performed in 7 hospitals in Korea. Candidate risk factors were age, sex, histology, Ann Arbor stage at diagnosis, number of prior treatments, time to progression (TTP) after autoSCT, bone marrow involvement, Eastern Cooperative Oncology Group (ECOG) performance status (PS), donor type, stem cell source, conditioning regimens of alloSCT, serum lactate dehydrogenase (above 250 IU/L), serum albumin (above 3.0 g/dL), and acute graft-versus-host disease (aGvHD). Between August 1998 and March 2009, 38 patients received alloSCT. Median age was 37 (range, 17–54) years. Male to female ratio was 26:12. Eighteen patients (47.4%) had B-cell lymphoma and 20 patients (52.6%), T/NK-cell lymphoma. Before alloSCT, patients had received median 4 (range, 2–7) prior treatments including autoSCT. Median TTP after autoSCT was 5.9 (range, 0.8–35.8) months. Twenty four patients (63.2%) received stem cells from related donors and 14 patients (36.8%) from unrelated donors. Median number of CD34+ cells infused was 5.41 × 106 (range, 0.86 × 106-16.60 × 106) /kg. Eighteen patients (47.4%) underwent a myeloablative conditioning and 20 patients (52.6%), a reduced intensity conditioning. During a median follow-up of 45.2 (range, 1.3–137.1) months, 24 patients (63.2%) experienced treatment failure and 22 patients (57.9%) died. Median event-free survival (EFS) was 6.3 (95% confidence interval (CI), 4.3–8.4) months. Median overall survival (OS) was 19.0 (95% CI, 3.8–34.2) months. Estimated 5-year survival rate was 35.0% (Figure). Treatment response was evaluable in 30 patients. Response rate was 73.3%; complete remission (CR) was achieved in 20 patients (66.7%) and partial response in 2 patients (6.7%). Grade 3 or 4 renal toxicity developed in 6 patients (15.8%), grade 3 or 4 hepatic toxicity in 15 patients (39.5%) including veno-occlusive disease (VOD) in 6 patients (15.8%), aGvHD in 13 patients (34.2%), and neutropenic fever in 34 patients (89.5%) including documented sepsis in 11 patients (28.9%). TRM was reported in 8 patients (21.1%). Causes of TRM were infection in 7 patients and VOD in 1 patient. In univariate analysis, no significant association was found with treatment response. By contrast, EFS was related to stage (p=0.039), TTP after autoSCT (p=0.033), and PS (p 〈 0.001). OS was associated with stage (p=0.037), number of prior treatments (p=0.049), TTP after autoSCT (p=0.032), PS (p 〈 0.001), and serum albumin (p=0.016). On the other hand, aGvHD was not associated with EFS (p=0.545) and OS (p=0.476). Multivariate analysis demonstrated that stage IV (hazard ratio (HR) 2.85 (95% CI, 1.13–7.22); p=0.027) and ECOG PS 2 (HR 3.94 (95% CI, 2.08–7.47); p 〈 0.001) were significant factors for EFS and that stage IV (HR 3.28 (95% CI, 1.19–9.04); p=0.022), ECOG PS 2 (HR 5.26 (95% CI, 2.22–12.48); p 〈 0.001), and serum albumin above 3.0 g/dL (HR 0.15 (95% CI, 0.03–0.63); p=0.010) were significant factors for OS. TRM was associated with PS (p=0.010) and serum albumin (p=0.040) by univariate analysis. Multivariate analysis showed that ECOG PS 2 was the only significant factor for TRM (relative risk (RR) 11.77 (95% CI, 1.43–97.01); p=0.022). ECOG PS 2 was also a significant factor for documented sepsis (RR 7.14 (95% CI, 1.08–47.42); p=0.042). DLI was performed in 8 patients who failed alloSCT. After median 1.5 (range, 1–6) cycles of DLI, 2 patients achieved CR. Grade III or IV aGvHD developed in these patients. By contrast, among 6 patients who failed to achieve CR, aGvHD developed in 2 patients. In conclusion, alloSCT is a viable option for patients with NHL who failed autoSCT despite high TRM. Stage and PS were significant factors for EFS and OS. Serum albumin was a significant factor for OS. In patients with ECOG PS 2, alloSCT should be avoided and novel treatment approaches should be offered due to high risk of TRM. DLI after failure of alloSCT showed promising results, which supports the presence of graft-versus-lymphoma effect. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 6
    In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 90, No. 12 ( 2011-12), p. 1409-1418
    Type of Medium: Online Resource
    ISSN: 0939-5555 , 1432-0584
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2011
    detail.hit.zdb_id: 1458429-3
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  • 7
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 21, No. 2 ( 2015-02), p. 342-349
    Type of Medium: Online Resource
    ISSN: 1083-8791
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2015
    detail.hit.zdb_id: 3056525-X
    detail.hit.zdb_id: 2057605-5
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  • 8
    In: Acta Haematologica, S. Karger AG, Vol. 113, No. 4 ( 2005), p. 220-227
    Abstract: This retrospective study compared the results of reduced-intensity conditioning stem cell transplantation (RIST) and a conventional myeloablative regimen (CST) followed by allogeneic peripheral blood stem cell transplantation. In this respect, 63 RISTs and 41 CSTs were performed at 5 transplantation centers in Korea between April 1998 and December 2002. The RIST group had more adverse pretransplant characteristics. More aggressive diseases, like acute myeloid or lymphoblastic leukemia, were included in the CST group, while the RIST group included more indolent diseases, like chronic myeloid leukemia or myeloma (p 〈 0.001). The incidence of acute graft-versus-host disease (GVHD) grades 2–4 was 29.1 and 57.9% for the RIST and CST groups, respectively (p = 0.010), yet the incidence of chronic GVHD was similar in the two groups (57.4 vs. 71.9%). With a median follow-up of 13 months (0.5–61 months, 17 months in 52 survivors), the 3-year overall (OS) and disease-free survival (DFS) was similar in the RIST and CST groups (p = 0.965 for OS, p = 0.545 for DFS). In a multivariate analysis, RIST (p = 0.010), good performance status (p = 0.006) and a higher CD34+ cell dose (p = 0.008) were all identified as independent favorable prognostic factors for OS. Accordingly, in the current study, RIST produced equivalent or acceptable results compared with CST in terms of OS. Therefore, a prospective randomized trial of RIST and CST is warranted.
    Type of Medium: Online Resource
    ISSN: 0001-5792 , 1421-9662
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2005
    detail.hit.zdb_id: 1481888-7
    detail.hit.zdb_id: 80008-9
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  • 9
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 5007-5007
    Abstract: Background: Although it has been reported that the incidence of acute GVHD (aGVHD) and early non-relapse mortality (NRM) after HLA-identical sibling BMT are different between Japanese and other ethnicities, including white American, African American and Irish populations (Oh, Blood.2005), there has been no previous comparison among Asian countries. Patients and Methods: We retrospectively surveyed the data of 1933 patients (pts) (996 Korean and 937 Japanese) who underwent allo-Tx for leukemia or MDS between Jan, 2000 and Dec, 2005. The median age of the pts was 37 yrs (range, 16–70; 34 yrs vs 43 yrs, respectively) and the median follow-up of surviving pts was 1046 days (11–2435). Unexpectedly, the pts’ backgrounds, including age, underlying disease, disease status at Tx, stem cell source, donor type, No. of HLA-mismatched (MM) antigen/allele, conditioning regimen, in vivo T-cell depletion with ATG or Campath-1H and GVHD prophylaxis were significantly different between the two groups. Results: (Table) In a multivariate analysis, Tx from a serologically HLA-1-antigen MM donor, Tx from an unrelated donor (URD), pts with high-risk disease at Tx, no in vivo T-cell depletion and a conditioning regimen that included TBI ≥ 10 Gy were associated with an increased risk of grade II–IV aGVHD. Overall, race was not a risk factor for grade II–IV (P=0.19) or III–IV (P=0.98) aGVHD. The incidence of chronic GVHD (cGVHD) in Japanese was significantly lower than that in Korean (P=0.016). In a multivariate analysis, Tx from a genetically HLA-allele MM donor, Tx from an URD, pts with performance status 2–4 at Tx, pts with high-risk disease at Tx, pts with ALL, female to male Tx and pts’ age ≥ 40 yrs were associated with poor OS. Race was not a risk factor for OS. The incidence of relapse adjusted for the underlying disease status was associated with grade II–IV aGVHD (RR 0.75, 95% CI 0.61–0.94, P=0.010), but not cGVHD (P=0.63). Conclusions: Despite their different medical backgrounds, our data confirmed that the biology of GVHD is very similar between these two Asian populations, and this provides a uniform foundation for large-scale clinical studies in the region. Korean (n=996) Japanese (n=937) Grade II–IV/III–IV aGVHD 37%/15% 44%/19% Median onset of aGVHD day 28 day 21 cGVHD 60% 47% 3-yr OS in standard/high risk 70%/42% 65%/41% NRM 25% 30% Relapse 25% 24%
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
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  • 10
    In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 92, No. 8 ( 2013-8), p. 1101-1110
    Type of Medium: Online Resource
    ISSN: 0939-5555 , 1432-0584
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2013
    detail.hit.zdb_id: 1458429-3
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