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  • 1
    In: Cytotherapy, Elsevier BV, Vol. 12, No. 7 ( 2010-11), p. 881-887
    Type of Medium: Online Resource
    ISSN: 1465-3249
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2010
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  • 2
    In: Blood, American Society of Hematology, Vol. 126, No. 1 ( 2015-07-02), p. 42-49
    Abstract: There is a strong negative association between comorbidities at diagnosis and overall survival. There is no negative effect of comorbidities on remission rates and progression to advanced phases in CML.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 3
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 156-156
    Abstract: Introduction: Early prediction of outcome using response-related predictive landmarks has become a major paradigm in the clinical management of chronic myeloid leukemia (CML). Several studies have shown the predictive impact of 10% BCR-ABLIS at 3 and 6 months for different tyrosine kinase inhibitors. The question, which landmark should define treatment failure and determine treatment intervention has been discussed vividly. However, an objective analysis of quality criteria for different early prognostic landmarks is lacking up to now. Here we compare sensitivity, specificity and the proportion of later disease progressions predicted by 3-month and 6-month landmarks in imatinib-treated patients of the CML-study IV. Methods: A total of 1,303 newly diagnosed patients were assigned to an imatinib-based treatment arm of CML-Study IV by April 2010. Median follow-up was 7.1 years. The number of molecular assessments was as follows: n=789 (at 6 months), n=692 (at 3 months) and n=301 (at 3 months and at diagnosis, without pretreatment). Gene expression levels were determined by quantitative RT-PCR. At 3 and 6 months, a BCR-ABL ratio was calculated using ABL as reference gene and standardized according to the international scale (BCR-ABLIS). In addition, at 3 months and at diagnosis a BCR-ABL ratio was calculated using beta-glucuronidase (GUS) as reference gene in order to ensure linearity of measurement at diagnosis. The log reduction at 3 months was calculated from the BCR-ABL ratio at 3 months and at diagnosis. Due to the time-dependent nature of censored survival data, the sensitivity and specificity at eight years were calculated using the method by Heagerty et al. (Biometrics 2000). Overall survival (OS) is defined by the absence of death from any reason, progression-free survival (PFS) is defined as survival in the absence of progression to accelerated or blastic phase. Landmark analyses were performed to compare survival outcomes according to Kaplan-Meier. Results:Comparing the 10% BCR-ABLIS landmark at 3 and 6 months, 8-year OS and PFS rates are equal or comparable (table). In contrast, sensitivity and specificity differ substantially with an advantage in favor of sensitivity for the 3-month landmark and in favor of specificity for the 6-month landmark. This difference is paralleled by a smaller proportion of high-risk patients and less progressions identified by the 6-month landmark. From a clinical point of view the 6-month landmark is not only less than half as sensitive, moreover a treatment intervention at 6 months might also prevent less progressions due to the delay of 3 months. The half-log reduction landmark at 3 months is as sensitive as 10% BCR-ABLIS at the same time. However, it shows improved specificity and defines the smallest proportion of high-risk patients. Conclusion: The 10% BCR-ABLIS landmark, which is currently defining treatment failure at 6 months according to European LeukemiaNet (ELN) criteria, fails to detect the majority of patients with later disease progression. Less than a half-log reduction of individual baseline BCR-ABL transcript levels at 3 months on treatment identifies patients with later progressions as sensitive but with higher specificity as compared to 10% BCR-ABLIS. Abstract 156. Table Prognostic landmark 8-year OS (%) 8-year PFS (%) P-value for PFS Sensitivity to predict progression (%) Specificity to predict progression (%) High-risk patients Disease progressions classified as high-risk / total 3 months (n=692) 10% BCR-ABLIS 88 vs. 96 82 vs. 90 0.001 41.1 74.6 191 (28%) 32/74 (43%) 6 months (n=789) 10% BCR-ABLIS 88 vs. 96 84 vs. 95 0.001 18.2 93.8 95 (12%) 17/74 (23%) 1% BCR-ABLIS 90 vs. 97 89 vs. 97 〈 0.001 39.6 68.6 291 (37%) 46/74 (62%) 3 months (n=301) 0.5-log reduction 81 vs. 95 75 vs. 94 〈 0.001 42.6 86.9 48 (16%) 10/24 (42%) Disclosures Hanfstein: Novartis: Research Funding; Bristol-Myers Squibb: Honoraria. Hehlmann:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding. Saussele:Novartis: Honoraria, Research Funding, Travel Other; Bristol-Myers Squibb: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria, Travel, Travel Other. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Neubauer:MedUpdate: Honoraria, Speakers Bureau. Kneba:Novartis: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pfirrmann:Novartis: Consultancy; Bristol-Myers Squibb: Honoraria. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; ARIAD: Honoraria, Research Funding; Pfizer: Consultancy, Research Funding. Müller:Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 4
    In: Leukemia Research, Elsevier BV, Vol. 29, No. 6 ( 2005-6), p. 673-677
    Type of Medium: Online Resource
    ISSN: 0145-2126
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2005
    detail.hit.zdb_id: 2008028-1
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  • 5
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 15_suppl ( 2015-05-20), p. 7041-7041
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
    detail.hit.zdb_id: 2005181-5
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  • 6
    In: Acta Haematologica, S. Karger AG, Vol. 114, No. 2 ( 2005), p. 91-94
    Abstract: The effect of the underlying disease and chemotherapy on megakaryopoiesis has not been extensively studied in children with acute lymphoblastic leukemia (ALL) during and at the end of therapy. Using a serum-free assay, we assessed the megakaryocyte (Mk) colony formation in vitro from bone marrow mononuclear cells of 25 children with ALL during chemotherapy and shortly after the cessation of it. Twelve children with solid tumors without bone marrow involvement and cord blood from 10 full-term normal vaginal deliveries were used as controls. A significant reduction in the number of Mk colonies was observed at diagnosis of ALL, and Mk colony formation remained lower than controls throughout the different phases of leukemia treatment. Our study suggests that defects in megakaryopoiesis of children with ALL in long-term remission may persist during chemotherapy and at least shortly after the end of it.
    Type of Medium: Online Resource
    ISSN: 0001-5792 , 1421-9662
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2005
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  • 7
    In: Cytotherapy, Elsevier BV, Vol. 14, No. 6 ( 2012-07), p. 701-706
    Type of Medium: Online Resource
    ISSN: 1465-3249
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2012
    detail.hit.zdb_id: 2071176-1
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  • 8
    Online Resource
    Online Resource
    Georg Thieme Verlag KG ; 2022
    In:  Hämostaseologie Vol. 42, No. 05 ( 2022-10), p. 337-347
    In: Hämostaseologie, Georg Thieme Verlag KG, Vol. 42, No. 05 ( 2022-10), p. 337-347
    Abstract: In premenopausal women treatment with direct oral anticoagulants (DOACs) can be associated with an increased risk of heavy menstrual bleeding (HMB) compared with vitamin K antagonists. These findings come from retrospective or prospective single-center studies and post hoc analysis of regulatory studies in which HMB was not a predefined safety outcome. In most of these publications, there is a lack of information about the use of different contraceptive methods which can influence HMB. Another limitation is the various definitions of HMB, which makes comparison between studies regarding the incidences of HMB difficult. Therefore, prospective studies are urgently needed to investigate the severity and duration of unaffected menstrual bleeding under oral anticoagulation independently of oral contraceptives or intrauterine devices. An ongoing multicenter German registry is aiming to compare the incidence of unaffected HMB in consecutive women of reproductive age (18–50 years) treated with different DOACs because of venous thromboembolism. When HMB occurs during oral anticoagulation, management includes interruption or dose reduction of anticoagulation with the danger of recurrent venous thrombosis, switch to another oral anticoagulant, or additional use of the antifibrinolytic agent tranexamic acid with the potential risk of thrombosis. Concomitant use of either oral hormonal contraceptive therapy or hormone-releasing intrauterine systems can also reduce HMB.
    Type of Medium: Online Resource
    ISSN: 0720-9355 , 2567-5761
    Language: English
    Publisher: Georg Thieme Verlag KG
    Publication Date: 2022
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  • 9
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2567-2567
    Abstract: Allogeneic HSCT has been established as the only curative treatment option for patients with chronic myeloid leukemia (CML). However, after the advent of tyrosine kinase inhibitors (TKI) the proportion of transplanted patients has decreased dramatically. After imatinib failure, most patients receive second or third line therapy with alternative TKIs. In an important minority of patients, SCT is performed too late as more patients are transplanted after disease progression to accelerated phase or blast crisis than in first chronic phase (CP, Saussele et al. BMT 2012). A possible reason is the uncertainty on long-term outcome after SC T in the imatinib-era as reports are scarce and accurate comparative data on the impact of salvage TKI therapy vs allogeneic transplantation are missing. We therefore investigated the outcome of transplanted patients within the CML study IV. Preliminary data were published (Saussele et al. BLOOD 2010). Here, we sought to re-evaluate the outcome of these patients with a longer follow-up. In July 2002, the German CML-Study Group activated a prospective randomized trial comparing different imatinib based strategies in CP CML. Elective early HSCT was considered for patients with EBMT score 0–1 for those with high disease risk, and after imatinib failure. By the end of March 2012, 1551 patients were randomized. In 2008, HSCT was documented in 84 patients. One patient was not evaluable any more due to withdrawal of consent. 52 patients were male (65%), 23 high risk patients (28%) according to the Euro CML score. Median age at diagnosis was 37 years (range, 16-62), median time to HSCT was 12.6 months (range, 3.5-54). EBMT score was 0-1 in 8 (10%), 2 in 10 (12%), 3-4 in 44 (55%), and 〉 =5 in 18 patients (23%), three patients were missing. Median follow-up after HSCT was 86.9 months (range, 0.3-122). Based on the indication for HSCT three groups are defined: 1) early HSCT, n= 19 (23%; low EBMT score (n=9), high risk patients (n=7), patient request (n=3); 2) HSCT after imatinib failure or intolerance in first CP (n=36 patients, 43%), and 3) HSCT in second CP or higher, accelerated phase or blast crisis (n=28 patients, 34%). 26 patients died, 13 deaths were transplant related, 9 CML related 4 either unrelated or unknown. Overall survival rate at 6 years after HSCT was 89% (95%-confidence interval (CI): 72-99%) for group 1, 80% (95%-CI: 66-91%) for group 2, and 49% (31-68%) for group 3. A matched pair analysis could be performed for 53 transplanted patients of group 1 and 2. To each of the transplanted patients two imatinib-treated patients could be matched with regard to age, sex, risk profile, disease phase, and interval to transplantation. Median follow up of this population was 87 months. Overall survival after 8 years was 83% (95%-CI: 71-92%) for transplanted and 89% (95%-CI: 82-94%) for imatinib treated patients without any statistical difference. Data from this update with a longer follow-up support the role of HSCT as an attractive and important salvage therapy for CML patients with imatinib failure or intolerance. In a matched pair comparison of transplanted and non-transplanted patients, we did not find significant differences. Disclosures Saussele: Novartis: Honoraria, Research Funding, Travel Other; Bristol-Myers Squibb: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria, Travel, Travel Other. Müller:Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Hanfstein:Novartis: Research Funding; Bristol-Myers Squibb: Honoraria. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; ARIAD: Honoraria, Research Funding; Pfizer: Consultancy, Research Funding. Pfirrmann:Novartis: Consultancy; Bristol-Myers Squibb: Honoraria. Hehlmann:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 10
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 3996-3996
    Abstract: Current evidence indicates that acquired genetic instability in chronic myeloid leukemia (CML) as a consequence of the balanced reciprocal translocation t(9;22)(q34;q11) or the variant translocation t(v;22) and the resulting BCR-ABL fusion causes the continuous acquisition of additional chromosomal aberrations (ACA) and mutations and thereby progression to accelerated phase and blast crisis (BC). At least 10% of patients in chronic phase (CP) CML show ACA already at diagnosis and more than 80% of patients acquire ACA during the transformation process into BC. Therefore, alterations at diagnosis as well as acquisition of chromosomal changes during treatment are considered as a poor prognostic factor. Differences in progression-free survival (PFS) and overall survival (OS) have been detected depending on the type of ACA. Patients with major route ACA (+8, i(17)(q10), +19, +der(22)t(9;22)(q34;q11)) and with other alterations like -X, del(1)(q21), del(5)(q11q14), +10, -21 at diagnosis resulting in an unbalanced karyotype have a worse outcome. Patients with minor route ACA (for example reciprocal translocations other than the t(9;22)(q34;q11) (e.g. t(1;21), t(2;16), t(3;12), t(4;6), t(5;8), t(15;20)) resulting in a balanced karyotype show no differences in OS and PFS compared to patients with the standard translocation, a variant translocation or the loss of the Y chromosome (Fabarius et al., Blood 2011). Here we compare the type of chromosomal changes (i.e. balanced vs. unbalanced karyotypes) during the course of the disease from CP to BC aiming to provide a valid parameter for future risk stratification. Patients and Methods Clinical and cytogenetic data available from 1,346 out of 1,524 patients at diagnosis (40% females vs. 60% males; median age 53 years (range, 16-88)) with Philadelphia and BCR-ABL positive CP CML included until March 2012 in the German CML-Study IV (a randomized 5-arm trial to optimize imatinib therapy) were investigated. ACA were comparatively analyzed in CP and in BC. Results At diagnosis 1,174/1,346 patients (87%) had the standard t(9;22)(q34;q11) only and 75 patients (6%) had a variant t(v;22). Ninety-seven patients (7%) had additional cytogenetic aberrations. Of these, 44 patients (3%) lacked the Y chromosome (-Y) and 53 patients (4%) had ACA. Regarding the patients with ACA thirty-six of the 53 patients (68%) had an unbalanced karyotype and 17/53 patients (32%) a balanced karyotype. During the course of the disease 73 patients (out of 1,524 patients) developed a BC during the observation time (5%). Cytogenetic data were available in 52 patients with BC (21 patients with BC had no cytogenetic analysis). Three patients had a normal male or female karyotype after stem cell transplantation. Nine patients showed the translocation t(9;22)(q34;q11) or a variant translocation t(v;22) (six and three patients, respectively) only and in 40 patients ACA could be observed in BC (40/49 (82%)). Out of these 40 patients with ACA, 90% showed an unbalanced karyotype whereas only 10% of patients had a balanced karyotype. No male patient in BC showed the loss of the Y chromosome pointing to a minor effect of this numerical alteration on disease progression. Conclusion We conclude that patients with CML and unbalanced karyotype at diagnosis are under higher risk to develop CML BC compared to patients with balanced karyotypes or compared to patients without ACA. In BC, 90% of CML patients showed unbalanced karyotypes (only 68% of CML patients at diagnosis have unbalanced karyotypes) supporting the hypothesis that the imbalance of chromosomal material is a hallmark of disease progression, representing the natural history of the disease from CP to BC and indicating therefore a strong prognostic impact. Consequently, different therapeutic options (such as intensive therapy or stem cell transplantation) should be considered for patients with unbalanced karyotypes in CP CML at diagnosis. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Hehlmann:BMS: Consultancy, Research Funding; Novartis: Research Funding. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding, travel Other; BMS: Consultancy, Honoraria, Research Funding; Pfizer : Consultancy, Honoraria; Ariad : Consultancy, Honoraria. Müller:Ariad: Honoraria; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Saussele:Pfizer: Honoraria; BMS: Honoraria, Research Funding, Travel, Travel Other; Novartis: Honoraria, Research Funding, Travel Other.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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    detail.hit.zdb_id: 80069-7
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