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  • 1
    In: Haematologica, Ferrata Storti Foundation (Haematologica), Vol. 104, No. 5 ( 2019-05), p. 955-962
    Type of Medium: Online Resource
    ISSN: 0390-6078 , 1592-8721
    Language: English
    Publisher: Ferrata Storti Foundation (Haematologica)
    Publication Date: 2019
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  • 2
    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
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2014
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  • 3
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1681-1681
    Abstract: Abstract 1681 Introduction: The prognostic impact of different levels of molecular remission (BCR-ABL transcript expression according to International Scale, IS) at various time points on survival under imatinib treatment is still unclear. Whereas recently published data from the IRIS trial described relevant milestones at 6, 12, and 18 months for event-free and progression-free survival (PFS; Hughes et al., Blood 2010), little is known about an association of molecular response with overall survival (OS). The aim of this evaluation of the German CML Study IV was to elucidate the risk of disease progression and death as a function of the depth of molecular response in order to provide guidance in the interpretation of BCR-ABL levels in the clinical setting. Methods: 1,340 patients (median age 52 years, range 16–88, 60% male) were recruited into the randomized German CML Study IV and treated with an imatinib-based therapy as follows: imatinib 400 mg/d, n=381; imatinib 800 mg/d, n=399; imatinib 400 mg/d + interferon alpha, n=402; imatinib 400 mg/d + low-dose cytarabine, n=158. A total of 1,262 patients with typical b2a2 and b3a2 BCR-ABL transcripts were evaluable. Molecular responses were assessed in 811, 764, 671, and 619 patients at 6, 12, 18, and 24 months, respectively. Disease progression was defined as accelerated phase or blastic phase, or death from any reason. Landmark analyses and log-rank tests for OS and PFS were performed according to the achievement of different BCR-ABL response levels at different time points. Results: Patients were grouped according to the degree of molecular response ( 〈 0.1%, 0.1%-1%, 1%-10%, 〉 10% BCR-ABL IS) at each of the 4 time points and evaluated for 5-year OS and PFS. Estimated 5-year OS for the different molecular response categories was: 97% vs 96% vs 90% vs 88% (6 months, p=0.009); 96% vs 95% vs 89% vs 69% (12 months, p 〈 0.001); 98% vs 97% vs 92% vs 66% (18 months, p 〈 0.001); 97% vs 96% vs 96% vs 68% (24 months, p 〈 0.001). Applying the 4 response categories revealed estimated 5-year PFS of 97% vs 96% vs 91% vs 86% (p=0.004) at 6 months, 97% vs 92% vs 89% vs 72% (p 〈 0.001) at 12 months, 99% vs 95% vs 90% vs 77% (p 〈 0.001) at 18 months, and 97% vs 97% vs 93% vs 65% (p 〈 0.001) at 24 months (s. Table). Conclusions: Faster and deeper response to imatinib-based treatment revealed to be associated with improved overall and progression-free survival. Inferior OS and PFS can be deducted from the synopsis of BCR-ABL expression and treatment duration, e.g. 〉 1% BCR-ABL IS at 6 months or 12 months might be, and 〉 10% BCR-ABL IS should be a trigger for a treatment change. Thereby this analysis might provide decision guidance for alteration or continuation of primary imatinib treatment. Disclosures: Schnittger: Münchner Leukämie Labor: Equity Ownership. German CML Study Group:EU: Research Funding; BMBF: Research Funding; Novartis: Research Funding; Deutsche Krebshilfe: Research Funding; Roche: Research Funding; Essex: 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: 2011
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  • 4
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3773-3773
    Abstract: Abstract 3773 Introduction: The vast majority of chronic myeloid leukemia (CML) patients express a BCR-ABL fusion gene mRNA encoding a 210 kDa tyrosine kinase which is constitutively activated and hence the mainspring of leukemic transformation. Two typical mRNA variants exist that differ in the presence or absence of the 75 basepair BCR exon 14: the e13a2 (lacking exon 14, also known as “b2a2”) and the e14a2 BCR-ABL transcript (“b3a2”). The significance of the additional 25 amino acid residues of the e14a2 BCR-ABL oncoprotein was extensively studied in the pre-imatinib era. However, the influence of the BCR-ABL transcript variant on the individual disease phenotype and outcome remained controversial and is still undefined in the imatinib era. Patients and methods: A total of 1,104 patients (median age 52 years, range 16–85, 40% female) expressing typical BCR-ABL transcript types (e13a2, n=447; e14a2, n=491; e13a2 and e14a2, n=166) were included in the randomized German CML study IV and treated with an imatinib based therapy consisting of imatinib 400 mg, imatinib 800 mg and combinations of standard dose imatinib with interferon alpha and low-dose cytarabine. The type of BCR-ABL transcript was defined by multiplex PCR. BCR-ABL expression was determined by quantitative RT-PCR and standardized according to the international scale (IS). Cytogenetic response was determined by conventional metaphase analyses. Response landmarks were defined according to European LeukemiaNet criteria, MR4 was defined as BCR-ABL IS ≤ 0.01% Results: No differences regarding age, sex and Euro risk were observed. A significant difference was observed comparing white blood cells (90,400/μl vs. 69,100/μl, p 〈 0.001) and platelets (293,000/μl vs. 424,000/μl, p 〈 0.001) at diagnosis (median, e13a2 vs. e14a2, respectively) indicating a distinct phenotype. No significant difference was observed regarding spleen size, basophils, eosinophils, blasts or adverse events under imatinib. Molecular response as determined by a transcript independent quantitative PCR assay was superior in e14a2 patients as compared to e13a2 patients (median time to major molecular response, MMR 1.5 years vs. 1.2 years, p 〈 0.001; median time to MR4 4.2 years vs. 2.5 years, p 〈 0.001). No difference was observed with regard to the achievement of a complete cytogenetic remission (CCyR). The superior molecular response rate of e14a2 patients did not translate into differences in progression free survival (PFS) or overall survival (OS). Conclusion: Distinct initial blood counts suggest a different phenotype of e13a2 and e14a2 driven CML. MMR and MR4 are achieved earlier by e14a2 patients whereas no difference was observed with regard to PFS and OS. Disclosures: Schnittger: Münchner Leukämie Labor: Equity Ownership. Haferlach:Münchner Leukämie Labor: Equity Ownership. German CML Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; BMBF: Research Funding; EU: Research Funding; Roche: Research Funding; Essex: 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: 2011
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  • 5
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3762-3762
    Abstract: Abstract 3762 Introduction: The EUTOS Score was developed and validated as a prognostic tool for the achievement of complete cytogenetic response (CCR) at 18 months for chronic phase (CP) CML patients under imatinib therapy. The score identifies high-risk patients not reaching CCR at 18 months with a positive predictive value of 34% and a specificity of 92% using only two variables, peripheral blood basophils and spleen size at diagnosis (Hasford et al. Blood 2011). We sought to evaluate the clinical impact of the EUTOS score to predict molecular response. Therefore, we analyzed the EUTOS score with patients from the German CML-Study IV, a randomized 5-arm trial (imatinib 400 mg vs. imatinib 800 mg vs. imatinib in combination with interferon alpha vs. imatinib in combination with araC vs. imatinib after interferon failure). Results: From July 2002 to December 2010, 1,502 patients with BCR-ABL positive CML in CP were randomized. 129 patients with imatinib after interferon alpha and 36 other patients had to be excluded (14 due to incorrect randomization or withdrawal of consent, 22 with missing baseline information). 1,337 patients were evaluable for overall and progression-free survival (OS and PFS), 1,252 for molecular responses. 749 of these patients were part of the score development sample. Therefore cytogenetic analyses are not described here. By EURO score, 36% of patients (n=475) were low risk, 51% (n=681) intermediate risk, and 12% (n=167) high risk. The EUTOS score was low risk in 88% (n=1163) and high risk in 12% (n=160). The high-risk patients differed between the two scores: EUTOS high-risk patients were classified according to EURO score in 12% as low (n=19), in 45% as intermediate (n=68) and in 43% as high risk (n=73). Patients with high, intermediate, and low risk EURO score achieved MMR in 22, 16, and 13 months and CMR4 (BCR-ABL 〈 =0.01%) in 59, 41, and 34 months. P-values for low vs. intermediate risk groups were borderline only (0.03 for MMR and 0.04 for CMR4), whereas p-values for high vs. low/intermediate risk groups were for both molecular response levels 〈 0.001. At 12 months the proportion of patients in MMR was 38%, 46%, 54% for high, intermediate, and low risk patients, respectively. Similar results were observed with the Sokal score. Patients with high risk EUTOS score achieved deep molecular responses (MMR and CMR4) significantly later than patients with low risk EUTOS score (MMR: median 21.0 vs. 14.8 months, p 〈 0.001, Fig. 1a; CMR4: median 60.6 vs. 37.2 months, p 〈 0.001, Fig. 1b). The proportions of patients achieving MMR at 12 months were significantly lower in the EUTOS high-risk group than in the EUTOS low-risk group (30.8% vs. 50.6%, p 〈 0.001). OS after 5 years was 85% for high and 91% for low risk patients (p=n.s.), PFS was 85% and 90%, respectively. Conclusions: The EUTOS score clearly separates CML patients also according to MMR and CMR4 (MR4). The new EUTOS score should be used in future trials with tyrosine kinase inhibitors in CML. Disclosures: Neubauer: Novartis: Honoraria, Research Funding; Roche: Research Funding. Kneba:Hoffmann La Roche: Honoraria. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Hochhaus:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. German CML Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; BMBF: Research Funding; EU: Research Funding; Roche: Research Funding; Essex: 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: 2011
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  • 6
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 783-783
    Abstract: Abstract 783FN2 Introduction: The advent of second generation tyrosine kinase inhibitors (TKI) in the front line treatment setting of chronic myeloid leukemia (CML) has tightened the evaluation of imatinib response. Early assessment of response markers might identify slow responders harboring a BCR-ABL positive clone with an inferior susceptibility to tyrosine kinase inhibition. This group of patients could benefit from an early dose escalation or a change of treatment to a second generation TKI thus avoiding the risk of disease progression. Therefore we sought to evaluate the impact of molecular and cytogenetic response levels after 3 months of imatinib treatment on the further course of disease. Patients and methods: A total of 1,340 patients (median age 52 years, range 16–88, 40% female) were included into the randomized German CML study IV and treated with an imatinib based therapy consisting of imatinib 400 mg/d (n=381), imatinib 800 mg/d (n=399) and combinations of standard dose imatinib with interferon alpha (n=402) and low-dose cytarabine (n=158). Median follow-up was 4.7 years (range 0–9). Molecular response after 3 months was assessed in 743 patients, cytogenetic response in 498 patients. The BCR-ABL expression was determined by quantitative RT-PCR and standardized according to the international scale (BCR-ABL IS). Only patients expressing typical BCR-ABL transcripts (b2a2, b3a2, b2a2 and b3a2) were considered. Cytogenetic response was determined by conventional metaphase analysis. Disease progression was defined by the incidence of accelerated phase, blastic phase or death from any reason. A landmark analysis was performed for progression free survival (PFS) and overall survival (OS). Results: Disease progression was observed in 149 patients (11.1%), 127 patients died (9.5%). After 3 months of treatment the median BCR-ABL IS was 2.6% (0-100), the median proportion of Philadelphia chromosome positive metaphases (Ph+) was 8% (0-100). The BCR-ABL landmarks of 1% and 10% after 3 months of imatinib both proved to discriminate significantly for PFS and OS: BCR-ABL IS 〈 1% (n=233) vs. ≥1% (n=486), p=0.041 for PFS, p=0.048 for OS; BCR-ABL IS 〈 10% (n=524) vs. ≥10% (n=195), p=0.004 for PFS and p=0.001 for OS. A stratification in 3 risk groups according to the achievement of a BCR-ABL IS of 〈 1%, 1–10% and 〉 10% after 3 months resulted in a significant difference between the poor risk group ( 〉 10%, n=195) and the intermediate risk group (1-10%, n=291): p=0.038 for PFS and p=0.012 for OS. The difference between the intermediate risk group and the good risk group ( 〈 1%, n=233) was not significant. The five year survival probability was 97%, 94% and 87% for the good, intermediate and poor risk group, respectively. Cytogenetic response landmarks after 3 months of imatinib were also predictive for PFS and OS: Ph+ ≤35% (n=362) vs. Ph+ 〉 35% (n=123), p=0.022 for PFS, p=0.043 for OS; Ph+ ≤65% (n=401) vs. Ph+ 〉 65% (n=84), p=0.004 for PFS and p=0.011 for OS. A 3 group stratification did not reach statistical significance. Conclusions: The achievement of molecular and cytogenetic response landmarks after 3 months of imatinib treatment is predictive for long term progression free and overall survival. At 3 months a BCR-ABL IS of 10% or more is associated with a 5-year overall survival of 87% suggesting an early change of treatment, whereas a BCR-ABL IS of 1% or less indicates a favorable 5-year overall survival of 97%. Disclosures: Schnittger: Münchner Leukämie Labor: Equity Ownership. Haferlach:Münchner Leukämie Labor: Equity Ownership. German CML Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; BMBF: Research Funding; EU: Research Funding; Roche: Research Funding; Essex: 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: 2011
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  • 7
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 67-67
    Abstract: Abstract 67 Dose optimized imatinib (IM) at doses of 400– 800mg has been shown to induce faster and deeper cytogenetic and molecular – responses than standard IM (400mg/day). Since complete molecular remission (CMR 4.5) identifies a subgroup of patients who may stay in remission even after discontinuation of treatment, it was of interest to analyse whether CMR 4.5 is reached faster with dose optimized IM and whether CMR 4.5 correlates with survival. CMR 4 and CMR 4.5 are defined as ≤ 0.01% BCR-ABL IS or ≥ 4. log reduction and ≤ 0.0032% BCR-ABL IS or ≥ 4.5 log reduction, respectively, from IRIS baseline as determined by real-time PCR. CML-Study IV is a five arm randomized study of IM 400 mg vs IM 400 mg + IFN vs. IM 400 mg + Ara C vs. IM after IFN failure vs. IM 800 mg. In the IM 800 arm, a 6 weeks run in period at IM 400 mg was followed by a dose increase to 800 mg and then by a dose reduction according to tolerability. Grade 3 or 4 adverse effects (AE) were to be avoided. From July 2002 to March 2012 a total of 1551 patients with newly diagnosed chronic phase CML were randomized of whom 1525 were evaluable. Median age was 52 years, 88% were EUTOS low risk, 12% high risk, 36% were Euro score low risk, 52% intermediate and 12% high risk, 38% were Sokal low risk, 38% intermediate and 24% high risk. 113 patients were transplanted, 246 received 2nd generation TKI. 152 patients have died, 90 of CML or unknown reasons, 62 of not directly CML-related causes. After a median observation time of 67,5 months 6 years OS was 88.2% and PFS 85.6%. CCR, MMR, CMR 4 and CMR 4,5 were achieved significantly faster with dose optimized IM (400 – 800 mg). No significant differences in remission rates were observed between IM 400 mg and the combination arms IM 400 mg + IFN and IM 400 mg + Ara C, whereas IM after IFN failure thus far yielded significantly slower response rates. After 4 years CCR rates were for IM 400, IM 400 + IFN, IM 400 + Ara C, IM 400 after IFN, and IM 800, 80%, 75%, 73%, 59% and 80%, respectively, MMR rates 84%, 77%, 82%, 61% and 88%, CMR 4 rates 57%, 55%, 55%, 40% and 65%, and CMR 4.5 rates 40%,42%, 42%, 28% and 52%, respectively. CMR 4 was reached after a median of 27 months with IM 800 and 41.5 months with IM 400. CMR 4.5 was reached after a median of 41.5 months with IM 800 and 63 months with IM 400. EUTOS low risk patients reached all remissions faster than EUTOS high risk patients. The differences of CMR 4 rates between IM 800 and IM 400 at 3 years were 13% and at 4 years 8%, and of CMR 4.5 rates at 3 years 10% and at 4 years 13%. Grade 3 and 4 AE were not different between IM 400 and dose optimized IM 800. Independent of treatment approach, CMR 4 and more clearly CMR 4.5 at 3 years predicted better OS and PFS, if compared with patients without CMR 4 or CMR 4.5, respectively. CMR 4 and 4.5 were stable. After a median duration of CMR 4 of 3.7 years only 4 of 792 patients with CMR 4 have progressed. Life expectancy with CMR 4 and 4.5 was identical to that of the age matched population. We conclude that dose optimized IM induces CMR 4.5 faster than IM 400 and that CMR 4 and CMR 4.5 at 3 years are associated with a survival advantage. Dose optimized IM may provide an improved therapeutic basis for unmaintained treatment discontinuation in patients with CML. Disclosures: Hehlmann: Novartis: Research Funding. Müller:Novartis, BMS: Consultancy, Honoraria, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Hochhaus:Novartis, BMS, MSD, Ariad, Pfizer: Consultancy Other, 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: 2012
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  • 8
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3746-3746
    Abstract: Abstract 3746 Introduction: The increase of overall survival in chronic myeloid leukemia (CML) requires closer long-term observation in the face of a potential carcinogenicity of tyrosine kinase inhibitors (TKIs). Preclinical studies with imatinib in rats showed neoplastic changes in kidneys, urinary bladder, urethra, preputial and clitoral glands, small intestine, parathyroid glands, adrenal glands, and nonglandular stomach. Two epidemiologic studies on patients with chronic myeloproliferative neoplasms (CMPN) and CML (Frederiksen H et al., Blood 2011; Rebora P et al., Am J Epidemiol 2010) found an increased risk of secondary malignancies compared with the general population independent of treatment. In contrast, in a recent analysis of patients with CML and CMPN treated with TKI (Verma D et al., Blood 2011) a decreased risk of secondary malignancies was reported. Aims: To further elucidate the risk of TKI treated CML patients for the development of secondary malignancies we analysed data of the CML study IV, a randomized 5-arm trial (imatinib 400 mg vs. imatinib 800 mg vs. imatinib 400 mg in combination with interferon alpha vs. imatinib 400 mg in combination with AraC vs. imatinib 400 mg after interferon failure). Patients and methods: From February 2002 to April 2012, 1551 CML patients in chronic phase were randomized, 1525 were evaluable. Inclusion criteria allowed the history of primary cancer if the disease was in stable remission. Forty-nine malignancies were reported in 43 patients before the diagnosis of CML. If relapses occurred within 5 years after diagnosis of primary cancer they were not considered for further analysis. Median follow-up was 67.5 months. Age-standardized incidence rates were calculated from the age-specific rates using the European standard population (1976). Results: In total, 67 secondary malignancies in 64 patients were found in CML patients treated with TKI (n=61) and interferon alpha only (n=3). Twelve of these patients developed neoplasms after diagnosis of a primary cancer before diagnosis of CML, 5 patients with metastases or recurrence of the first malignancy (range of diagnosis 5–19 years after primary cancer). Median time to secondary malignancy was 2.5 years (range 0.1–8.3 years). The types of neoplasms were: prostate (n=9), colorectal (n=6), lung (n=6), non Hodgkin's lymphoma (NHL; n=7), malignant melanoma (n=5), skin tumors (basalioma n=4 and squamous cell carcinoma n=1), breast (n=5), pancreas (n=4), kidney (n=4), chronic lymphocytic leukemia (n=3), head and neck (n=2), biliary (n=2), sarcoma (n=2), and esophagus, stomach, liver, vulva, uterus, brain, cancer of unknown origin (each n=1). With these numbers the age-standardized incidence rates of secondary malignancies in CML patients were calculated: 534 cases per 100,000 for men (confidence interval [350;718]), and 582 for women (confidence interval [349;817] ). The incidence rates of the general population in Germany were 450 and 350 cases, respectively (“Krebs in Deutschland 2007/2008”, 8th ed., Robert Koch Institute, 2012). The incidence rate of NHLs was higher for CML patients than for the general population but this is not significant. Conclusions: In our cohort, the incidence rate of secondary neoplasms in CML patients was slightly increased compared to the general population. The most common secondary malignancies in CML patients under treatment were cancers of the skin, prostate, colon, lung and NHL. Since the occurrence of secondary neoplasia increases over time, long-term follow-up of CML patients is warranted. Disclosures: Müller: Novartis, BMS: Consultancy, Honoraria, Research Funding. Hochhaus:Novartis, BMS, MSD, Ariad, Pfizer: Consultancy Other, Honoraria, Research Funding. Hehlmann:Novartis: 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: 2012
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  • 9
    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
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2014
    detail.hit.zdb_id: 1458429-3
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  • 10
    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
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2017
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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