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  • Liu, Kai-Yan  (9)
  • Wang, Yu  (9)
  • Medizin  (9)
  • 1
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 2902-2902
    Kurzfassung: Introduction ADAM28, a member of the ADAM family of metalloproteinases, is over-expressed in several human tumors and is related to cell proliferation and metastasis. Our previous study has demonstrated that the expression level of ADAM28 is significantly elevated in patients with relapsed acute lymphoblastic leukemia, which was associated with poor prognosis. However, the impact of ADAM28 on relapse and the prognosis of patients with AML remains unclear. Aims: To investigate the effect of ADAM28 on the growth and dissemination of leukemia cells and to identify the prognostic significance of ADAM28 levels in patients with AML. Methods and results From 2012-2013, 189 de novo AML patients were prospectively enrolled in this study. The expression of ADAM28 in the leukemic cells of AML patients at diagnosis was significantly higher than that in the donor BM cells. No correlations were found between the expression level of ADAM28 and either FAB classification or cytogenetic risk groups. However, the expression levels of ADAM28 differed significantly between patients suffering a relapse and those remaining in CR. Furthermore, the ADAM28 levels in the cerebrospinal fluid (CSF) of patients with central nervous system leukemia (CNSL) were significantly higher than those in patients without CNSL. These data suggested that ADAM28 levels might be related to the incidence of relapse in patients with AML. We further investigated whether ADAM28 could impact the proliferation, migration and invasiveness of leukemic cells in vitro. Primary AML cells with high ADAM28 expression levels have better proliferation, migration and invasion capacities than those with low ADAM28 expression levels. Knocking out ADAM28with aCRISPR/Cas9 lentivirus significantly inhibited the proliferation, migration and invasion in leukemic cells. The increased expression of ADAM28 lead to more prolific IGFBP-3 degradation and IGF-IR phosphorylation, whereas the ADAM28 knock out cells resulted in significant down-regulation of IGFBP-3 degradation and IGF-IR phosphorylation in leukemic cells. In a xenotransplantation mice model, primary cells with elevated ADAM28 expression have improved engraftment ability in hematopoietic tissue and enhanced dissemination into nonhematopoietic tissue compared with primary cells with lower ADAM28 expression. Blocking ADAM28 expression in leukemic cells ameliorated AML growth and dissemination after xenotransplantation. We then analyzed the prognosis of the cohort of AML patients. Patients were divided into a high expression group and low expression group according to the ADAM28 expression cutoff value based on the status of relapse. The cumulative incidence of relapse (CIR) and overall survival (OS) after a 3-year follow-up were used to evaluate the prognosis. The CIR after 3 years was significantly higher in the ADAM28 high expression group (p 〈 0.0001); the higher CIR translated into a significantly worse OS (p=0.001). Moreover, when separately considering the impact of ADAM28 on prognosis within the risk stratifications, patients with high ADAM28 expression levels had a significantly higher CIR and worse OS in the favorable-risk group but not in the intermediate or poor-risk group. Because the patients with favorable risk were predominantly inclined to chemotherapy, the ADAM28 high expression patients presented a significantly higher CIR and worse OS than the low expression patients in the chemotherapy subgroup, whereas the prognosis did not differ significantly with the ADAM28 expression level in patients receiving HSCT. Conclusion ADAM28 improved the proliferation, migration and invasion of leukemic cells in which the IGF pathway was involved. High expression of ADAM28 enhanced the growth and dissemination of AML in vivo. ADAM28 expression levels also identified a new subgroup at higher risk for relapse and poor prognosis in favorable-risk AML patients, and this subgroup of patients which were allocated to chemotherapy, might benefit more from HSCT. Combining the expression level of ADAM28 with the existing risk stratification standard may be a more precise and preferable approach in predicting therisk of relapse in AML patients. Disclosures No relevant conflicts of interest to declare.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
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    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2016
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 13-13
    Kurzfassung: Introduction Immune thrombocytopenia (ITP) is an acquired, organ-specific, autoimmune disease and one of the most common bleeding disorders seriously endangering human health. Glucocorticoids and intravenous immunoglobulin are first-line treatments recommended by guidelines for patients with ITP. However, approximately 50%-85% of patients relapse during the first year of treatment. In addition, long-term use of glucocorticoids increases the risk for dose- and time-dependent glucocorticoid-related complications and serious side effects. Therefore, in-depth studies investigating new solutions for the first-line treatment of ITP are urgently needed. Tacrolimus is a calcineurin inhibitor, which forms a complex by binding to FK506-binding protein. It is currently widely used in the prevention of graft-versus-host disease for organ transplantation as well as for the treatment of autoimmune diseases. In addition to recent retrospective studies and case reports demonstrating its effectiveness in ITP, tacrolimus has been shown to improve anti-platelet antibody-mediated thrombocytopenia in mice, suggesting it may be a potential treatment for ITP. The aim of this study was to compare two first-line treatment options for ITP-a standard glucocorticoid-only regimen versus tacrolimus in combination with a standard glucocorticoid regimen-to determine which could help patients achieve stable platelet counts faster and experience a longer duration of remission. Methods This open-label, randomized, phase 2 trial, enrolled adult ITP patients from seven different tertiary medical centers in China. Elderly patients had confirmed, newly diagnosed, treatment-naive ITP, platelet counts & lt;30×10 9/L, or & lt; 50×10 9/L and significant bleeding symptoms (World Health Organization bleeding scale ≥ 2). Eligible patients were randomly assigned 1:1 with an interactive web-based response system to receive either oral tacrolimus (initial 0.03 mg/kg/day and maintain blood concentration at 3-5 ng/mL for 12 weeks) plus high-dose dexamethasone (HD-DXM) or HD-DXM monotherapy for 12 weeks. DXM (40 mg) was administered orally daily for 4 consecutive days to both study arms. The 4-day course of DXM was repeated on days 11-14 in patients who lacked response by day 10. The primary endpoint was 6-month sustained response (SR), defined as platelet count maintained & gt;50×10 9/L without any additional ITP-modifying therapy at the 6-month follow-up. Key secondary endpoints included initial response by day 14 (OR, platelet count ≥30×10 9/L and at least 2-fold increase in baseline platelet count and absence of bleeding; and CR, platelet count ≥ 100×10 9/L), duration of response, bleeding scores, and adverse events (AEs). This trial was registered with ClinicalTrials.gov (NCT04747080). Results Total 140 patients newly diagnosed with ITP were randomly assigned to either the tacrolimus plus HD-DXM (n=72) or HD-DXM monotherapy (n=68) groups. At the 6-month follow-up, the proportion of patients exhibiting SR was significantly higher in the tacrolimus plus HD-DXM group than in the HD-DXM monotherapy group (65.3% vs 42.6%, p= 0.007). Of the 140 patients with ITP (males accounted for 48.6%), the mean age was 32.8 years, the mean platelet count was 16.7×10 9/L. The combination group exhibited a higher 14-day early remission rate than the monotherapy group (76.4% vs 55.9%, P=0.001). Significantly fewer treatment failures occurred in patients randomly assigned to the combination group(19.4% vs 38.2%, P=0.0014). During the follow-up period, fewer patients in the combination group experienced relapse than in the monotherapy group; the median time to relapse was 77 days (Tacrolimus+HD-DXM) vs 36 days (HD-DXM). The combination group exhibited a lower proportion of bleeding events and a lower bleeding score. The incidence of serious AEs, rescue therapy, and treatment side effects were similar between the two groups, and treatment was well tolerated by all patients, with no grade 4 AEs or treatment-related deaths reported. There was no statistically significant difference in the incidence of treatment-related AEs between the two groups. Conclusions Low-dose tacrolimus plus HD-DXM was an effective and safe treatment for ITP as first-line therapy and elicited a sustained prolonged response in adults. This therapy may be a new treatment option for adult patients with ITP. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: It includes information or discussion of off-label drug use of tacrilimus.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2021
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
    In: Blood, American Society of Hematology, Vol. 121, No. 20 ( 2013-05-16), p. 4056-4062
    Kurzfassung: Risk stratification treatment of t(8;21) acute myeloid leukemia may decrease relapse and improve long-term survival. Allo-HSCT benefited high-risk patients, but impaired the survival of low-risk patients.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2013
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 6 ( 2019-03-15), p. 1737-1748
    Kurzfassung: Although myeloablative HLA haploidentical hematopoietic stem cell transplantation (haplo-HSCT) following pretransplant anti-thymocyte globulin (ATG) and granulocyte colony-stimulating factor (G-CSF) stimulated grafts (ATG+G-CSF) has been confirmed as an alternative to HSCT from HLA-matched sibling donors (MSD), the effect of haplo-HSCT on postremission treatment of patients with acute myeloid leukemia (AML) with intermediate risk (int-risk AML) who achieved first complete remission (CR1) has not been defined. Patients and Methods: In this prospective trial, among 443 consecutive patients ages 16–60 years with newly diagnosed de novo AML with int-risk cytogenetics, 147 patients with molecular int-risk AML who achieved CR1 within two courses of induction and remained in CR1 at 4 months postremission either received chemotherapy (n = 69) or underwent haplo-HSCT (n = 78). Results: The 3-year leukemia-free survival (LFS) and overall survival (OS) were significantly higher in the haplo-HSCT group than in the chemotherapy group (74.3% vs. 47.3%; P = 0.0004 and 80.8% vs. 53.5%; P = 0.0001, respectively). In the multivariate analysis with propensity score adjustment, postremission treatment (haplo-HSCT vs. chemotherapy) was an independent risk factor affecting the LFS [HR 0.360; 95% confidence interval (CI), 0.163–0.793; P = 0.011], OS (HR 0.361; 95% CI, 0.156–0.832; P = 0.017), and cumulative incidence of relapse (HR 0.161; 95% CI, 0.057–0.459; P = 0.001) either in entire cohort or stratified by minimal residual disease after the second consolidation. Conclusions: Myeloablative haplo-HSCT with ATG+G-CSF is superior to chemotherapy as a postremission treatment in patients with int-risk AML during CR1. Haplo-HSCT might be a first-line postremission therapy for int-risk AML in the absence of HLA-MSDs. Haplo-HSCT might be superior to chemotherapy as a first-line postremission treatment of intermediate-risk AML in CR1.
    Materialart: Online-Ressource
    ISSN: 1078-0432 , 1557-3265
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    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2019
    ZDB Id: 1225457-5
    ZDB Id: 2036787-9
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 1309-1309
    Kurzfassung: Although acute myeloid leukemia (AML) with t (8; 21) translocation generally belongs to the favorable-risk AML subtypes, relapse occurs in about 40% of cases and long-term ( 〉 5years) survival less than 50%. KIT-mutation (KIT+) and minimal residual disease (MRD) levels have been demonstrated as two most important risk factors in several retrospective studies. Until now, only two prospective studies (Our AML05 trial; French CBF-2006 trial) have assessed their respective prognostic values (Zhu HH, et al. Blood 2013; 121:4056; Jourdan E, et al. Blood 2013; 121:2213). We found both KIT+ and MRD were independent risk factors for relapse, but Joundan et al found only MRD rather than KIT+ was sole prognostic factor for relapse in multivariate anaysis. Both studies did not perform a comprehensive subgroup analysis combining the two factors, and risk-adopt postremission treatment might also affect this assessment. Therefore, we performed a subgroup analysis combining KIT mutation and MRD in a prospective protocol AML05 to answer which is more important to predict outcomes of t(8;21)AML. Methods From July, 2005, to Jan, 2013, 114 patients with t (8; 21) AML after achieving complete remission were included in this analysis. KIT mutations in exons 17 and 8 were screened using the direct sequencing method. MRD was detected using quantitative PCR to detect the RUNX1/RUNX1T1 transcript. MRD-positive (MRD+) was defined as 〈 3 log reduction of RUNX1/RUNX1T1 transcript from baseline after second consolidation therapy. Sixty-two patients received high-dose cytarabine-based consolidation chemotherapy (CT) or autologous hematopoietic stem-cell transplantation (auto-HSCT), and 52 patients received allogeneic HSCT (allo-HSCT). Results When receiving CT/auto-HSCT as postremission treatment, KIT+ patients (n=19) had a higher 3 year cumulative incidence of relapse (CIR) than KIT-patients (n=43) (94.4% vs. 38.2%, p 〈 0.0001). Similar results also found in MRD+ (n=19) and MRD- (n=43) patients (CIR 92.9% vs. 46.6%, p 〈 0.0001). Among KIT+ patients, a very high relapse rate was found in both MRD+ and MRD-patients (CIR, 100% vs.88.9%). However, among KIT-patients, MRD+ patients had a significant higher relapse rate than MRD-patients (CIR, 84.4% vs.26.3%, p=0.0006). When pooling KIT+ and or MRD+ into one group (KIT+/MRD+), this group had a significant higher relapse rate than KIT-MRD- group ( 94.4% vs. 26.3%, p 〈 0.0001), However, the prognostic values of KIT and MRD was lost when patients received allo-HSCT (CIR of KIT+/MRD+ and KIT-MRD-, 23.8% vs. 15.6%, p=0.47). Similar results were also been found in disease-free survival (DFS) and overall-survival (OS). Multivariate analysis revealed that KIT+, MRD+, and treatment (allo-HSCT or CT/auto-HSCT) were three independent prognostic factors for relapse (all p 〈 0.0001), DFS (all p 〈 0.0001) and OS (p 〈 0.0001, p 〈 0.0001, p=0.007). Conclusions Both KIT status and MRD level were important to predict relapse of t (8;21) AML. KIT+ patients hold a very high relapse risk. Disclosures: No relevant conflicts of interest to declare.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2013
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 6
    In: Blood, American Society of Hematology, Vol. 117, No. 11 ( 2011-03-17), p. 3032-3040
    Kurzfassung: The relative merits of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and imatinib for chronic myelogenous leukemia in the accelerated phase (AP-CML) have not previously been evaluated. This cohort study was designed to compare the outcomes of imatinib (n = 87) versus allo-HSCT (n = 45) for AP-CML. A multivariate analysis of the total population revealed that a CML duration ≥ 12 months, hemoglobin 〈 100 g/L, and peripheral blood blasts ≥ 5% were independent adverse prognostic factors for both overall survival (OS) and progression-free survival (PFS). Both treatments resulted in similar survival in low-risk (no factor) patients, with 6-year event-free survival (EFS), OS, and PFS rates of more than 80.0%. Intermediate-risk (any factor) patients showed no difference in EFS and OS, but 6-year PFS rates were 55.7% versus 92.9% (P = .047) with imatinib versus allo-HSCT, respectively. Among high-risk (at least 2 factors) patients, imatinib was by far inferior to allo-HSCT, with 5-year EFS, OS, and PFS rates of 9.3% versus 66.7% (P = .034), 17.7% versus 100% (P = .008), and 18.8% versus 100% (P = .006), respectively. We conclude that allo-HSCT confers significant survival advantages for high- and intermediate-risk patients with AP-CML compared with imatinib treatment; however, the outcomes of the 2 therapies are equally good in low-risk patients. All trials were registered with the Chinese Clinical Trial Registry (www.chictr.org) as CHiCTR-TNC-10000955.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2011
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 7
    Online-Ressource
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    Springer Science and Business Media LLC ; 2023
    In:  Bone Marrow Transplantation Vol. 58, No. 5 ( 2023-05), p. 491-497
    In: Bone Marrow Transplantation, Springer Science and Business Media LLC, Vol. 58, No. 5 ( 2023-05), p. 491-497
    Materialart: Online-Ressource
    ISSN: 0268-3369 , 1476-5365
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    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2023
    ZDB Id: 2004030-1
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 8
    In: Blood, American Society of Hematology, Vol. 119, No. 23 ( 2012-06-07), p. 5584-5590
    Kurzfassung: We report the results of a prospective, patient self-selected study evaluating whether haploidentical related donor stem cell transplantation (HRD-HSCT) is superior to chemotherapy alone as postremission treatment for patients with intermediate- or high-risk acute myeloid leukemia (AML) in first complete remission (CR1). Among totally 419 newly diagnosed AML patients, 132 patients with intermediate- and high-risk cytogenetics achieved CR1 and received chemotherapy alone (n = 74) or HSCT (n = 58) as postremission treatment. The cumulative incidence of relapse at 4 years was 37.5% ± 4.5%. Overall survival (OS) and disease-free survival (DFS) at 4 years were 64.5% ± 5.1% and 55.6% ± 5.0%, respectively. The cumulative incident of relapse for the HRD-HSCT group was significantly lower than that for the chemotherapy-alone group (12.0% ± 4.6% vs 57.8% ± 6.2%, respectively; P 〈 .0001). HRD-HSCT resulted in superior survival compared with chemotherapy alone (4-year DFS, 73.1% ± 7.1% vs 44.2% ± 6.2%, respectively; P 〈 .0001; 4-year OS, 77.5% ± 7.1% vs 54.7% ± 6.3%, respectively; P = .001). Multivariate analysis revealed postremission treatment (HRD-HSCT vs chemotherapy) and high WBC counts at diagnosis as independent risk factors affecting relapse, DFS, and OS. Our results suggest that HRD-HSCT is superior to chemotherapy alone as postremission treatment for AML.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2012
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 9
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 162-162
    Kurzfassung: Abstract 162 Background and Aims. The relative merits of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for chronic myelogenous leukemia (CML) in the first chronic phase (CP) in the imatinib era have not previously been evaluated. This prospective cohort study was designed to compare the medical outcomes and quality of life (QOL), with imatinib versus allo-HSCT from an HLA-matched sibling donor for CML in the first CP including the early CP (ECP; a CML duration 〈 12 months) and the late CP (LCP; a CML duration ' 12 months). Patients and methods. From April 2001 to April 2010, patients treated consecutively at the Peking University People's Hospital, Peking University Institute of Hematology were nonrandomly assigned to treatment with imatinib or allo-HSCT according to whether the patient had an HLA-matched sibling donor; those with an HLA-identical sibling donor were assigned to the allo-HSCT group, and the others were assigned to the imatinib group. QOL of surviving patients still in the imatinib and allo-HSCT groups was measured by the Medical Outcomes Survey Short Form 36 (MOS SF-36) at the end of the study evaluation period in April 2011. Results. In total, 463 patients were recruited, 209 patients were assigned to the allo-HSCT group and 254 patients were assigned to the imatinib group, respectively.Based on a ten-year follow-up period, a multivariate analysis revealed that allo-HSCT was an independent adverse prognostic factor for event-free survival (EFS; estimated HR=2.4, P=0.002 and estimated HR=0.31, P 〈 0.001) and overall survival (OS; estimated HR=6.9, P 〈 0.001 and estimated HR=26.2, P=0.001) for the total population (n=463) and the patients in the ECP (n=348), and an independent favorable predictor of progression-free survival (PFS; estimated HR=3.2, P=0.020) for the total population. Imatinib was superior to allo-HSCT, with six-year EFS and OS rates of 83.6% vs. 76.6% (P=0.041) and 96.4% vs. 82.0% (P 〈 0.001), respectively, for the entire cohort and 90.3% vs. 74.3% (P=0.001) and 99.4% vs. 80.2% (P 〈 0.001), respectively, for the patients in the ECP, despite six-year PFS rates of 90.7% vs. 96.6% (P=0.014), respectively, for the entire cohort and 95.9% vs. 97.3% (P=0.303) respectively, for the patients in the ECP. Both treatments resulted in similar EFS and OS rates in those in the LCP (n=115), with a probability of six-year EFS rate of approximately 80% and six-year OS rate of more than 90%. More LCP patients in the imatinib group experienced relapse compared with those in the allo-HSCT group, with six-year PFS rates of 86.0% vs. 100% (P=0.035), respectively. There was no correlation between the EBMT risk score and EFS, OS or PFS in the patients receiving allo-HSCT. Among the 392 surviving patients who were invited to participate in the QOL survey, 295 (75.3%) patients including 180 of 218 (82.6%) in the imatinib group and 115 of 174 (66.1%) in the allo-HSCT group, respectively, completed the questionnaires. A multivariate analysis revealed that there was no correlation between the treatment mode and the physical health for the total, ECP and LCP population, however, allo-HSCT was one of the independent factors associated with good mental health (estimated HR=0.5, P 〈 0.001) in the ECP patients. The Physical Component Summary were comparable between the imatinib group and the allo-HSCT group, however, the Mental Component Summary of the patients experienced allo-HSCT were better than those receiving imatinib for the total (P=0.001), ECP (P=0.015) and LCP (P=0.010) population. Conclusions. We concluded that imatinib confers significant survival advantages and a desirable QOL and is superior to allo-HSCT as the first-line therapy for patients with CML in the ECP. All trials were registered with www.chictr.org as CHiCHTR-TNC-10000955. Disclosure: No relevant conflicts of interest to declare. Disclosures: No relevant conflicts of interest to declare.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2011
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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