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  • 1
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    Deep Molecular Response Is Reached by the Majority of Patients Treated With Imatinib, Predicts Survival, and Is Achieved More Quickly by Optimized High-Dose Imatinib: Results From the Randomized CML-Study IV
    American Society of Clinical Oncology (ASCO) ; 2014
    In:  Journal of Clinical Oncology Vol. 32, No. 5 ( 2014-02-10), p. 415-423
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 5 ( 2014-02-10), p. 415-423
    Abstract: Deep molecular response (MR 4.5 ) defines a subgroup of patients with chronic myeloid leukemia (CML) who may stay in unmaintained remission after treatment discontinuation. It is unclear how many patients achieve MR 4.5 under different treatment modalities and whether MR 4.5 predicts survival. Patients and Methods Patients from the randomized CML-Study IV were analyzed for confirmed MR 4.5 which was defined as ≥ 4.5 log reduction of BCR-ABL on the international scale (IS) and determined by reverse transcriptase polymerase chain reaction in two consecutive analyses. Landmark analyses were performed to assess the impact of MR 4.5 on survival. Results Of 1,551 randomly assigned patients, 1,524 were assessable. After a median observation time of 67.5 months, 5-year overall survival (OS) was 90%, 5-year progression-free-survival was 87.5%, and 8-year OS was 86%. The cumulative incidence of MR 4.5 after 9 years was 70% (median, 4.9 years); confirmed MR 4.5 was 54%. MR 4.5 was reached more quickly with optimized high-dose imatinib than with imatinib 400 mg/day (P = .016). Independent of treatment approach, confirmed MR 4.5 at 4 years predicted significantly higher survival probabilities than 0.1% to 1% IS, which corresponds to complete cytogenetic remission (8-year OS, 92% v 83%; P = .047). High-dose imatinib and early major molecular remission predicted MR 4.5 . No patient with confirmed MR 4.5 has experienced progression. Conclusion MR 4.5 is a new molecular predictor of long-term outcome, is reached by a majority of patients treated with imatinib, and is achieved more quickly with optimized high-dose imatinib, which may provide an improved therapeutic basis for treatment discontinuation in CML.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2013.49.9020
    RVK:
    XA 52760
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2014
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  • 2
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    Achievement Of a MR5.0 Within the Randomized CML-Study IV: Feasibility, Differences Between Treatment Arms, and Prognostic Implications
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 4008-4008
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    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 4008-4008
    Abstract: Depth of molecular remission on tyrosine kinase inhibitor (TKI) treatment is of rising importance for chronic myeloid leukemia (CML) patients (pts) with regard to possible treatment discontinuation and competing TKIs available to improve molecular response. At present, it is unknown which level of deep molecular response is necessary for optimal prognosis and for successfully stopping therapy. The aim of this work is both to evaluate the technical feasibility of molecular monitoring at the mentioned level and to search for factors allowing to predict MR5.0 in pts on imatinib (IM)-based treatment. Methods Real-time quantitative PCR on mRNA BCR-ABL transcripts in addition to total ABL transcripts as internal control has been performed on a LightCycler platform in 1,442 pts within the randomized CML-Study IV and adapted according to the International Scale (IS). In order to qualify for MR5.0 the BCR-ABLIS expression should meet one of the following criteria: a positive result ≤0.001% or a negative result with a minimum sample quality of 100,000 ABL copies (Cross et al., Leukemia 2012). Calculating cumulative incidences of remission or progression, the competing risks progression and/or death before possible progression were considered. Cox models were estimated for the multivariate analysis. Results In 1,198 of the 1,442 molecularly examined pts at least one sample fulfilled the sensitivity criteria for a MR5.0 (8,266 of 24,101 samples, 34.3%). Cumulative incidence of MR5.0 was 51% at 8 years. The median time to MR5.0 according to randomized treatment arms differed as follows: IM 800mg 79.7 months (mos), IM 400mg 95.0 mos, IM 400mg + IFNα 98.0 mos, IM 400mg + AraC 103.3 mos, IM 400mg after IFN failure 112.9 mos. A Cox model examining the different treatment arms compared to IM 400mg revealed a significantly higher chance for MR5.0 in the IM 800mg arm (HR 1.305, 95% CI 1.003-1.698, p=0.048). Baseline factors like thrombocytosis 〉 450/nl were associated with better responses (HR 1.701 compared to 〈 450/nl, 95% CI 1.405-2.059, p 〈 0.001) and higher leukocyte counts 〉 100/nl (HR 0.503 compared to 〈 50/nl, 95% CI 0.400-0.632, p 〈 0.001) and 50-100/nl (HR 0.746 compared to 〈 50/nl, 95% CI 0.591-0.942, p=0.014) with unfavorable responses. Other upfront factors like age, gender, blasts, eosinophils, hemoglobin, and EUTOS score did not significantly influence the probability for MR5.0. Taken all treatment arms together, our analyses have shown that the chance of achieving a MR5.0 by 8 years was considerably reduced if the pts had a BCR-ABLIS 〉 10% at 3 mos (40.2% vs 58.0%), 〉 1% at 6 mos (40.3% vs 68.7%), 〉 0.1% at 12 mos (37.7% vs 72.0%), and 〉 0.1% at 24 mos (21.5% vs 60.5%). Conclusion This evaluation of a large randomized trial reveals feasibility of MR5.0 detection in the majority of pts underlining the benefits of standardized molecular monitoring on the IS with optimized highly sensitive technologies. Baseline low leukocyte count, high thrombocyte count and high dose IM treatment are predictors of future MR5.0. Further, early molecular landmarks qualify for excellent outcome giving hope to a rising number of pts to successfully discontinue treatment and avoid possible side effects or comorbidities. Disclosures: Müller: Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. 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. Saussele:Novartis: Honoraria, Research Funding, Travel Other; BMS: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.4008.4008
    RVK:
    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 3
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    The Impact Of Balanced and Unbalanced Karyotypes On Prognosis Of CML: From Chronic Phase To Blast Crisis
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 3996-3996
    Details
    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
    URL: Article
    DOI: 10.1182/blood.V122.21.3996.3996
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 4
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    A Two-Fold Rise of BCR-ABL Transcript Levels Advises BCR-ABL Mutation Analysis in Imatinib-Treated Chronic Myeloid Leukemia (CML) - an Analysis of the Randomized CML-Study IV
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 3138-3138
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    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3138-3138
    Abstract: Introduction: The clonal selection of a mutant BCR-ABL positive clone can be observed in about one of two patients with imatinib-resistant chronic myeloid leukemia (CML). The early detection of BCR-ABL kinase domain mutations is crucial, since it allows to change the tyrosine kinase inhibitor (TKI) regimen in a timely manner and may therefore prevent disease progression and the accumulation of further genetic lesions. European LeukemiaNet (ELN) recommendations suggest a mutation analysis if optimal response criteria are not achieved at 3, 6, 12 or 18 months, or whenever a loss of optimal response occurs (Soverini et al., Blood 2011). Several attempts have been made to derive this indication from a specific increase of BCR-ABL levels. Here we report on the correlation of a rise in BCR-ABL transcript levels and the prevalence of BCR-ABL kinase domain mutations in imatinib-treated patients of the CML-Study IV. Methods: A total of 1,173 patients were enrolled until 2009 and randomized to one of four imatinib-based treatment arms. BCR-ABLIS of 988 patients was determined in 7,876 samples by quantitative RT-PCR in the central laboratory (median sample number per patient: 8.4, range 1-37; median follow up: 34 months, range 0-86), representing the eligible patients for the study. Thereby, the estimated intra-laboratory variance is assumed to be about 20%. A first rise of BCR-ABLIS to at least two-fold and 〉 0.1% between two samples of a patient's molecular course defined a sample suspected of bearing a mutant BCR-ABL positive clone. A mutation analysis was performed on this critical sample by direct sequencing of ABL exons 4 to 10. Results: A critical rise in BCR-ABLIS was observed in 231 of 988 patients (23%) after a median of 15.2 months on treatment (range 2.8-59.4). In the corresponding sample 33 mutant clones could be detected in 31 patients (13%). Thereby a steeper rise of BCR-ABLIS was correlated with a higher incidence of BCR-ABL mutations in the respective group (table). A total of 18 different mutations could be detected, the most frequent were: M244V, n=7 (21%); E255K, n=4 (12%); T315I, n=3 (9%); L248V, G250E, L387M and F486S, n=2 (6%), respectively. Mutations occur in a substantial proportion (8%) of patients with an only 2 to 3-fold rise of BCR-ABLIS transcript levels (table). Therefore, the most sensitive cut-off should be applied and mutation analysis may be triggered by a doubling of BCR-ABL transcripts at levels 〉 0.1% IS. Conclusion: BCR-ABL kinase domain mutations occur already in a substantial proportion of patients with a doubling of BCR-ABL transcript levels, which should determine mutation analysis. Table 1. Rise of BCR-ABL expression Patients (n) Patients with BCR-ABL mutations (n) Patients with BCR-ABL mutations (%) Inter-sample interval(median, days) 2 to 3-fold 72 6 8.3 98 3 to 5-fold 50 3 6.0 100 5 to 10-fold 39 4 10.3 99 10 to 100-fold 49 10 20.4 98 〉 100-fold 21 8 38.1 125 〉 2-fold (total) 231 31 13.4 101 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:Pfizer: Consultancy, Research Funding; ARIAD: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, 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
    URL: Article
    DOI: 10.1182/blood.V124.21.3138.3138
    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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    Optimizing Early Prediction Of Outcome In CML Using The Exact Decline Of BCR-ABL Transcript Levels Within 3 Months Of Imatinib Treatment As a Prognostic Marker
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 253-253
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    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 253-253
    Abstract: Early assessment of BCR-ABL transcript levels at 3 months allows the prediction of survival and may serve as a trigger for treatment intensification in CML patients with slow response to imatinib. The exact decline of BCR-ABL transcript levels within the first 3 months of treatment is defined by the ratio BCR-ABL transcripts at 3 months to BCR-ABL transcripts at baseline. This ratio might better reflect the individual biology of disease and its susceptibility to tyrosine kinase inhibition. Methods A total of 408 chronic phase CML patients (pts) with baseline and 3 month blood samples available in one single laboratory were investigated. Pts with pre-treatment before first blood sampling were excluded (imatinib with or without hydroxyurea, n=58; hydroxyurea only, n=49). A total of 301 evaluable pts (median age 52 years, range 18-85, 41% female) were treated with an imatinib-based therapy within the CML-Study IV. Median follow-up was 4.8 years. Transcript levels of BCR-ABL, total ABL, and beta-glucuronidase (GUS) were determined by quantitative RT-PCR. Exploratory landmark analyses were performed with regard to overall and progression-free survival (OS, PFS) to evaluate the prognostic significance of (i) BCR-ABL/GUS before treatment, (ii) the individual reduction of transcripts given by (BCR-ABL/GUS at 3 months) / (BCR-ABL/GUS before treatment), and (iii) the 3-month 10% BCR-ABLIS landmark. Results The median BCR-ABL/GUS ratio was 15.5% at diagnosis (0.06-107) and 0.63% at 3 months (0-84) reflecting a decline to the 0.04-fold (1.4 log reduction). i) No prognostic cut-off could be identified for BCR-ABL/GUS before treatment. ii) A reduction to the 0.35-fold of the initial BCR-ABL transcript level at diagnosis (0.46 log reduction) was identified as best cut-off according to a hazard ratio of 5.6 (95%-CI 2.3-13.4, p 〈 0.001 for PFS). Using this cut-off a high-risk group of 48 pts (16% of pts, 5-year PFS and OS: 77% and 83%) was separated from a good-risk group of 253 pts (84% of pts, 5-year PFS and OS: 96% and 98%). iii) As a comparison we investigated the 10% BCR-ABLIS landmark at 3 months with a hazard ratio of 2.4 (95%-CI 1.0-5.8, p=0.06 for PFS). With this landmark a high-risk group of 67 pts (22% of pts, 5-year PFS and OS: 87% and 90%) was separated from a good-risk group of 234 pts (78% of pts, 5-year PFS and OS: 95% and 97%). Conclusion A two-group risk stratification according to the individual reduction of BCR-ABL transcripts to the 0.35-fold of pre-treatment levels yields a superior separation of risk groups with a 5-year difference of 19% for PFS and 15% for OS. This predictive marker might identify patients at risk more precisely than 3-month 10% BCR-ABLIS. Disclosures: Hehlmann: BMS: Consultancy, Research Funding; Novartis: Research Funding. Saussele:Novartis: Honoraria, Research Funding, Travel Other; BMS: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding, Travel Other; BMS: Consultancy, Honoraria, Research Funding; ARIAD: Consultancy, Honoraria; Pfizer: Consultancy. Müller:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.253.253
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 6
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    The Cytogenetic Profile In Lymphoid and Myeloid CML Blast Crisis
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 1487-1487
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 1487-1487
    Abstract: In acute leukemias, specific cytogenetic aberrations frequently correlate with myeloid or lymphoid phenotype of blasts and influence risk stratification. In chronic myeloid leukemia (CML) blast crisis (BC) it is not clear whether myeloid or lymphoid phenotype of blasts could be distinguished by specific chromosomal aberrations and have prognostic value. At diagnosis of CML, major route additional cytogenetic aberrations (ACA) like +8, i(17)(q10), +19, +der(22)t(9;22)(q34;q11) and minor route ACA like -X, del(1)(q21), del(5)(q11q14), +10,-21, resulting in an unbalanced karyotype have been described to adversely affect 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 did not show differences in overall survival and progression free survival compared to patients with the standard translocation, a variant translocation or the loss of the Y chromosome. Aim of this study was to analyze the impact of the phenotype (myeloid or lymphoid) on time to BC and on cytogenetic pattern. Methods 73 out of 1524 evaluable patients (4.8%) randomized until March 2012 to the German CML-Study IV (a 5-arm trial to optimize imatinib therapy) progressed to BC. Cytogenetic data of 23 out of 32 patients with myeloid BC and 14 out of 21 patients with lymphoid BC were available. In 15 patients, cytogenetic analysis were missing whereas 2 and 3 patients had megakaryoblastic and mixed phenotype, respectively and were not considered in this analysis. Karyotypes of lymphoid and myeloid BC were divided in major route and minor route ACA and balanced and unbalanced karyotypes. Categorical covariates were compared with Fisher’s exact test, while continuous covariates were compared with the Mann-Whitney-Wilcoxon test. Survival probabilities after BC were compared using the log-rank test. Results Out of 23 patients with myeloid BC, 14 (61%) had major route unbalanced ACA (n=10) or minor route unbalanced ACA (n=4), 4 had minor route balanced ACA and 5 patients had the translocation t(9;22)(q34;q11) or a variant translocation t(v;22) without ACA.13 out of 14 (93%) patients with lymphoid BC had major route unbalanced (n=10) or minor route unbalanced ACA (n=3) and 1 had the standard translocation t(9;22)(q34;q11) only. Between myeloid and lymphoid BC, the difference in the distribution of unbalanced ACA was apparent, but not statistically significant (p=0.06). The most frequently observed major route ACA was trisomy 8 in both groups (7 vs. 6), +der (22)t(9;22)(q34;q11) was more frequently found in myeloid than lymphoid BC (6 vs. 2), +19 was found in both phenotypes (3 vs. 3) whereas an isochromosome i(17)(q10) and an isoderivative chromosome ider(22)t(9;22)(q34;q11) were less frequent and found only in myeloid BC (1 for each vs 0 for each aberration). In lymphoid BC, 5 of 14 patients (36%) had ACA which involved chromosome 7 (del(7)(q22) and -7) whereas in myeloid BC only 2 patients (9%) had -7 (p=0.08). The balanced karyotype with a translocation t(3;21)(q26;q22) and the translocation t(9;11)(p22;q23) described in acute myeloid leukemia was observed in 3 patients with myeloid CML (2 and 1, respectively) and in none with lymphoid phenotype. No differences were observed in time to BC for patients with lymphoid vs. myeloid BC (p=0.31, median time: 409 vs. 453 days) and survival after onset of BC (p=0.9, median time: 544 vs. 284 days). Conclusions The proportion of unbalanced karyotypes was higher in lymphoid than in myeloid BC. In lymphoid BC alterations of chromosome 7 were more often present whereas +der(22)t(9;22)(q34;q11) was observed more frequently in myeloid BC. The reciprocal translocations t(3;21)(q26;q22) and t(9;11)(p22;q23) described in acute myeloid leukemias were only observed in myeloid BC. However these cytogenetic differences do not seem to alter the course of BC. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Hehlmann:Novartis: Research Funding; BMS: Consultancy, Research Funding. Hochhaus:Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Travel Other. Müller:Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding; Ariad: Honoraria. 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
    URL: Article
    DOI: 10.1182/blood.V122.21.1487.1487
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 7
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    Final Evaluation of Randomized CML-Study IV: 10-Year Survival and Evolution of Terminal Phase
    American Society of Hematology ; 2017
    In:  Blood Vol. 130, No. Suppl_1 ( 2017-12-07), p. 897-897
    Details
    In: Blood, American Society of Hematology, Vol. 130, No. Suppl_1 ( 2017-12-07), p. 897-897
    Abstract: Background Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400mg/day (n=400) could be optimized by doubling the dose (n=420), adding IFN (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). Methods From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. The impact of patients' and disease factors on survival was prospectively analyzed. At the time of evaluation, at least 62% of patients still received imatinib, 26.2% were switched to 2nd generation tyrosine kinase inhibitors. Results After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival 80% and 10-year relative survival 92%. In spite of a faster response with IM800mg, the survival difference between IM400mg and IM800mg was only 3% at 5 years. In a multivariate analysis, the influence on survival of risk-group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs. other) was significant in contrast to any form of initial treatment optimization. Patients that reached the response milestones 3, 6 and 12 months, had a significant survival advantage of about 6% after 10 years regardless of therapy. The progression probability to blast crisis was 5.8%. Blast crisis was proceeded by high-risk additional chromosomal aberrations. Conclusions For responders, monotherapy with IM400mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients' and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease and blast crisis, more life-time can currently be gained by carefully addressing non-CML determinants of survival. Disclosures Hehlmann: Novartis: Research Funding; BMS: Consultancy. Saussele: Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Pfirrmann: BMS: Honoraria; Novartis: Honoraria. Krause: Novartis: Honoraria. Baerlocher: Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria. Bruemmendorf: Novartis: Research Funding. Müller: Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Jeromin: MLL Munich Leukemia Laboratory: Employment. Hänel: Roche: Honoraria; Novartis: Honoraria. Burchert: BMS: Honoraria. Waller: Mylan: Consultancy, Honoraria. Mayer: Eisai: Research Funding; Novartis: Research Funding. Link: Novartis: Honoraria. Scheid: Novartis: Honoraria. Schafhausen: Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Hochhaus: Incyte: Research Funding; MSD: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; ARIAD: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V130.Suppl_1.897.897
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2017
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    Adverse Events (AE) Under Imatinib Treatment Over 10 Years: Results From 1501 Patients Of The Randomized CML-Study IV
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 4012-4012
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 4012-4012
    Abstract: Tyrosine kinase inhibitors (TKI) have changed the natural course of CML. Their efficacy leads to normal life expectancy in the vast majority of patients. With the advent of 2nd generation TKI and the now available choice of drugs, safety issues have gained interest. We have used the randomized CML-Study IV for a long-term safety evaluation of imatinib. Study and Patients CML-Study IV comprises 1551 patients randomized to 5 treatment arms with 3 imatinib-based combinations and 2 different imatinib-dose schedules. 1501 patients have received imatinib and were evaluable. Median age at diagnosis was 53 years, 88% were EUTOS low risk. At the last evaluation (04/11/2013) 1003 patients still received imatinib, 164 had died, 275 were switched to a 2nd generation TKI, 106 were transplanted. The longest observation time was 11.5 years, the median observation time was 6.5 years, with a 10-year survival probability of 84 %. The median time to imatinib discontinuation has not been reached after 10.2 years. 80 patients are under observation for more than 10 years, 18 of these have discontinued imatinib. Out of the 1501 patients that had received imatinib, 1375 patients received imatinib as first-line treatment and had a sufficient documentation of treatment. Methods AE were reported at each follow-up visit. The CTC AE list of the NCI was used for coding of AE and severity grading. Additionally, for detection of hematologic AE lab results were screened for deviations from reference ranges. The AE were analyzed according to the “as treated” principle, using Kaplan-Meier curves (virtually no competing risks, almost all patients died after end of imatinib treatment). Only the first event of the respective type was considered. All analyses started at the first day of imatinib treatment and were censored when the patient discontinued imatinib, received another treatment or died. To assess the differences between men and women, Cox models were estimated. Results In 1137 out of 1375 patients (83%) non-hematologic AE (5160 singular events) were reported during imatinib treatment (all grades), in 322 grade 3/4 AE (23%) (645 singular events). At 3 years, probability of a non-hematologic AE (any grade) was already 76% (95%-CI: 73-79%), at 6 years 85% (95%-CI: 82-88%) and at 8 years 91% (Fig.1). The probability of grade 3/4 non-haematologic AE was 38% (95%-CI: 34-42%) at 6 years and 43% (CI: 37-48%) at 8 years. 156 patients reported hematologic grade 3/4 AE (187 singular events).The probability of hematologic grade 3/4 AE was 17% at 6 years (95%-CI: 15-21%) with most events observed during the first year of treatment (probability after one year 10.5%). The most frequently reported non-hematologic AE (all grades, any time) were gastrointestinal (6-year-probability 52%, 95%-CI: 48-56%), fluid overload or edema (6y-prob. 45%, 95%-CI: 40-49%), rash (6y-prob. 32%, 95%-CI: 28-36%), myalgia or arthralgia (6y-prob. 30%, 95%-CI: 27-34%), fatigue (6y-prob. 26%, 95%-CI: 22-29%), flu-like symptoms (6y-prob. 22%, 95%-CI: 19-26%), infections (6y-prob. 24%, 95%-CI: 20-28%) and neurological symptoms (6y-prob. 26%, 95%-CI: 22-29%). AE probability profiles over time have been generated for each AE (Figs. 2-3). For women the risk for non-hematologic events was increased 1.35-fold (95% CI: 1.18-1.55) for all grades (Figs. 1-3) and 1.13-fold (95% CI: 0.91-1.41) for grade 3/4, and 1.26-fold (95% CI: 0.91-1.71) for grade 3/4 hematologic AE. In 5 patients peripheral arterial occlusive disease grade 2 or 3 was reported, but none could be clearly assigned to imatinib (vascular risk profile of one patient incompletely reported). A definite association between any AE and death was not found. Conclusion As AE by definition may or may not be considered related to the medical treatment an exact assessment of the safety of imatinib is difficult. Most AE were recorded during the first three years with decreasing frequency later on. The increased AE risk in women was mostly grade 1/2 and is commonly seen also in other treatment areas. Given that no imatinib-related death was recorded and that grade 3/4 AE could typically be properly treated we consider imatinib as a safe, comparably well tolerated TKI even after prolonged treatment. After 10 years imatinib continues to be an excellent choice for the treatment of CML in most patients. Disclosures: Hehlmann: Novartis: Research Funding; BMS: Consultancy, Research Funding. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding, Travel Other; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria. Müller:Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding; Ariad: Honoraria. Saussele:Novartis: Honoraria, Research Funding, Travel Other; BMS: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.4012.4012
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 9
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    Impact of unbalanced minor route versus major route karyotypes at diagnosis on prognosis of CML
    Springer Science and Business Media LLC ; 2015
    In:  Annals of Hematology Vol. 94, No. 12 ( 2015-12), p. 2015-2024
    Details
    In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 94, No. 12 ( 2015-12), p. 2015-2024
    Type of Medium: Online Resource
    ISSN: 0939-5555 , 1432-0584
    URL: Article
    DOI: 10.1007/s00277-015-2494-9
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2015
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  • 10
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    Younger patients with chronic myeloid leukemia do well in spite of poor prognostic indicators: results from the randomized CML study IV
    Springer Science and Business Media LLC ; 2014
    In:  Annals of Hematology Vol. 93, No. 1 ( 2014-1), p. 71-80
    Details
    In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 93, No. 1 ( 2014-1), p. 71-80
    Type of Medium: Online Resource
    ISSN: 0939-5555 , 1432-0584
    URL: Article
    DOI: 10.1007/s00277-013-1937-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2014
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