GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
  • American Society of Hematology  (12)
  • Baerlocher, Gabriela M.  (12)
  • 1
    Online Resource
    Online Resource
    Therapy with Imatinib In Elderly CML Patients (〉65years): Results of the German CML-Study IV.
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 3411-3411
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3411-3411
    Abstract: Abstract 3411 Background: Dose of therapy and time to response may be different in the elderly as compared to younger patients with CML. This has been reported previously for interferon α (Berger et al., Leukemia 2003). For imatinib, contradictory results have been presented (Rosti et al. Haematologica 2007, Guliotta et al. Blood 2009). Aims: An analysis comparing dose-response relationship in patients more or less than 65 years (y) of age is warranted. Methods: We analysed the German CML-Study IV, a randomized 5-arm trial to optimize imatinib therapy by combination, dose escalation and transplantation. Patients older and younger than 65y randomized to imatinib 400 mg (IM400) or 800 mg (IM800) were compared with regard to time to hematologic, cytogenetic and molecular remissions, imatinib dose, adverse events (AEs) and overall survival (OS). Results: From July 2002 to April 2009, 1311 patients with Ph+ CML in chronic phase were randomized, 623 patients were evaluable, 311 patients for treatment with IM400 and 312 for IM800. 84 (27%) and 66 (21%), respectively, were older than 65 years. All patients were evaluable for hematologic, 578 (140 〉 65y and 438 〈 65y) for cytogenetic, and 600 (143 and 457, respectively) for molecular responses. Median age was 70y vs. 49y for IM400 and 69y vs. 46y for IM800. The median dose per day was lower for elderly patients with IM800 (517mg vs. 666mg) and the same with IM400 (400mg each). Patients' characteristics at baseline were evenly distributed in all groups regarding gender, follow-up, hemoglobin, platelet count and spleen size. Leukocyte counts were significantly lower in elderly patients (IM400: 50/nl vs. 78/nl, IM800: 36/nl vs. 94/nl). EURO score was different due to age in elderly patients (low risk: IM400: 11% vs. 43%, IM800: 14% vs. 42%; intermediate risk: IM400: 79% vs. 44% and IM800: 73% and 43%). There was no difference in cytogenetic and molecular analyses between treatment groups. With regard to efficacy, there was no difference for older patients in achieving a complete cytogenetic remission (CCR) and major molecular remission (MMR) if IM400 and IM800 were compared together. If treatment groups were analyzed separately, older patients treated with IM400 reached CCR and MMR statistically significant slower than younger patients (CCR: median 14.2 months vs. 12.1 months, p=0.019; MMR: median 18.7 months vs. 17.5 months, p=0.006). There was no difference with IM800 (CCR: median 7.7 months vs. 8.9 months, MMR: median 9.9 months vs. 10.0 months). 3y-OS for older patients 〉 65y was 94.7% and for patients 〈 65y was 96.1%. Some differences were observed in the safety analyses. 530 patients (IM400: 278, IM800: 252) were evaluated on common toxicity criteria (WHO). Some hematologic AEs were documented slightly more often in the elderly than in the younger patients: for IM400 anemia grade 1–2 (60 vs. 42%) and leukopenia grade 3–4 (5.6 vs. 1.4%) and for IM800 anemia grade 1–4 (64 vs.47% and 7.2 vs. 5.7%) and thrombocytopenia grade 3–4 (9.3 vs. 7.1%). Non hematologic AEs were more prominent in IM800 and were mainly gastrointestinal symptoms (IM400: 33 vs. 31%, IM800: 48 and 44%) and edema (IM400: 28 vs. 29%, IM800: 35 vs. 50%). There was no difference for grade 3/4 non-hematological AEs in older patients in both groups. Conclusions: Imatinib 400 mg and 800 mg are well tolerated also in the elderly. The IM800 dosage was more tolerability-adapted for the elderly, but there was no difference in reaching a CCR and MMR in contrast to the IM400 where a significantly slower response was detected in the elderly. Whether this difference is clinically relevant has yet to be determined. Updated results will be presented. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership, Research Funding. German CML-Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; Roche: Research Funding; BMBF: Research Funding; Essex: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.3411.3411
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    Major Route Additional Chromosomal Aberrations (ACA) Precede Increase of Blasts in CML: An Analysis of the German CML-Studies III and IIIA
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 1581-1581
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1581-1581
    Abstract: During the course of chronic myeloid leukemia (CML) progression to blast crisis (BC) is thought to be caused by genetic instability such as cytogenetic aberrations in addition to the translocation t(9;22)(q34;q11). We have shown previously that major route ACA indicate an unfavorable outcome (Fabarius et al., Blood 2011). We now investigate whether there is a correlation in time between appearance of major route ACA and increase in blast count. Methods: Cytogenetic data and blast count in the peripheral blood were available from 1,290 CML patients recruited to the German CML-studies III (621 patients) and IIIa (669 patients) from January 1995 to January 2004. Treatments were interferon-alpha-based or related allogeneic stem cell transplantation (HSCT). Presence of ACA and major route ACA was considered as a time-dependent covariate. Multivariate proportional hazards models were estimated taking Euro CML score, study III vs. IIIa and stem cell transplantability into account. Cumulative incidences of blast increases were calculated starting at the date of the first ACA or major route ACA, respectively, regarding death as a competing risk. Patients were censored at the date of HSCT with an unrelated donor. Results: 1,287 patients were evaluable with median observation times of 13 and 12 years and a 10-year survival of 48% and 61% in CML studies III and IIIa, respectively. 258 patients progressed to BC with a cumulative 10-year incidence of 20%. 195 patients displayed ACA during the course of disease. 45 patients (15.7%) showed ACA already at diagnosis. 44 patients showed unbalanced minor route, 29 balanced minor route aberrations, 23 -Y. 109 patients showed major route aberrations including 10 with other prior ACA. In a multivariate analysis on 1,257 patients, patients with ACA had a hazard ratio (HR) for a blast increase of between 2.0-2.2 (p 〈 0.001) for blast increases to ≥1%, ≥5%, ≥10%, ≥15%, ≥ 20% and ≥30% compared with patients without ACA (Table). When the same model was performed for major route ACA only at any time during disease, HRs of 2.2-2.7 (p 〈 0.001) were found. For ACA without major route ACA HRs were 1.6-2.1 (p 〈 0.001). In the multivariate analyses of major route ACA vs. no major route ACA a blast increase of 1-5% after diagnosis of major route ACA seems already indicative of progression. 5 years after the diagnosis of any ACA the cumulative incidence for a blast increase was 30% (95%- confidence interval (CI): 23-38%), of a major route ACA 40% (95%- CI: 28-49%). The 6-year probability of death without blast increase was 10%. 14 additional patients received an unrelated transplant of which 6 died. We conclude that ACA, particularly major route ACA, precede an increase of blasts. Major route ACA have to be considered as a prognostic indicator for disease progression at any time. Table 1. Blast increase to HR (univariate): ACA vs. no ACA HR(multivariate)*: ACA vs. no ACA HR (univariate): major route ACA vs. no major route ACA HR (multivariate)*: major route ACA vs. no major route ACA ≥30% 2.409 2.139 2.646 2.203 ≥20% 2.413 2.144 2.656 2.211 ≥15% 2.415 2.161 2.868 2.426 ≥10% 2.416 2.160 2.799 2.357 ≥5% 2.286 2.047 2.719 2.278 ≥1% 2.209 1.999 3.171 2.684 *adjusted to Euro-Score, study (III vs. IIIa) and transplantability Disclosures Saussele: ARIAD: Honoraria; BMS: Honoraria, Other: Travel grant, Research Funding; Pfizer: Honoraria, Other: Travel grant; Novartis Pharma: Honoraria, Other: Travel grant, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Scheid:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Baerlocher:Geron Corporation: Research Funding; Novartis: Research Funding. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Müller:BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Pfirrmann:BMS: Consultancy, Honoraria; Novartis Pharma: Consultancy, Honoraria. Baccarani:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hehlmann:BMS: Consultancy; Novartis Pharma: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.1581.1581
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    Superior CMR-Rates with Tolerability-Adapted Imatinib 800 Mg Vs. 400 Mg Vs. 400 Mg + IFN In CML: The Randomized German CML-Study IV
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 357-357
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 357-357
    Abstract: Abstract 357 Treatment of CML with imatinib of 400 mg can be unsatisfactory. Treatment optimization is warranted. The German CML-Study group has therefore conducted a randomized study comparing imatinib 800 mg vs 400 mg vs 400 mg + IFN. A significantly faster achievement of MMR at 12 months has been observed with imatinib 800 mg in a tolerability adapted manner and MMR by 12 months has been found to translate into better overall survival. Since stable CMR has been associated with durable off-treatment remissions we sought to analyse the impact of tolerability-adapted imatinib 800 mg on CMR and survival. Standardized determinations of molecular response and evaluation of its impact on outcome are goals of CML-Study IV. CMR4 is defined as a BCR-ABL/ABL ratio of 〈 0,01 on the International Scale. From July 2002 – April 30, 2009 1022 newly diagnosed patients with CML in chronic phase were randomized, 1012 were evaluable (338 with imatinib 800 mg, 324 with imatinib 400 mg, 350 with imatinib plus IFN). Median observation time was 40 months. The median average daily imatinib doses were 628 mg in the 800 mg arm and 400 mg in the 400 mg based arms. The actual median daily doses in the 800 mg arm per 3-months periods were: 555 mg, 737 mg, 613 mg, 600 mg, and 600 mg thereafter, reflecting the run–in period with imatinib 400 mg for 6 weeks in the first period and the adaptation to tolerability from the third 3-months period onwards. Median daily imatinib doses in the 400 mg arms were 400 mg throughout. Adaptation of imatinib dose in the 800 mg arm according to tolerability is reflected by similar higher-grade adverse events rates (WHO grades 3 and 4) with all treatments. Significantly higher remission rates were achieved with imatinib 800 mg by 12 months. The cumulative incidences of CCR by 12 months were 63% [95%CI:56.4-67.9] with imatinib 800 mg vs 50% [95%CI:43.0-54.5] with the two 400 mg arms. The cumulative incidences of MMR by 12 months were 54.8% [95%CI:48.7-59.7] with imatinib 800 mg vs 30.8% [95%CI:26.6-36.1] with imatinib 400 mg vs 34.7% [95%CI:29.0-39.2] with imatinib + IFN. The cumulative incidences of CMR4 compared with the MMR incidences over the first 36 months are shown in Table 1. Imatinib 800 mg shows superior CMR4 rates over the entire 36 months period, CMR4 is reached significantly faster with imatinib 800 mg as compared to the 400 mg arms. The CMR4 rates reach 56.8% by 36 months [95%CI:49.4-63.5] as compared to 45.5% with imatinib 400 mg [95%CI:38.7-51.0] and 40.5% with imatinib plus IFN [95%CI:34.6-46.3] . Most patients have stable CMR4 over the entire period. Time after start of treat-ment (months) Cumulative incidences MMR(%) CMR4 (%) IM400 n=306 D IM800 n=328 D IM400 +IFN n=336 IM400 n=306 D IM800 n=328 D IM400 +IFN n=336 6 8.6 9.5 18.1 9.7 8.4 3 0.7 3.7 1.3 2.4 12 30.8 24.0 54.8 20.1 34.7 7.5 12.3 19.8 7.4 12.4 18 50.3 18.1 68.4 14.3 54.1 21.2 12.2 33.4 9.8 23.6 24 63 13.0 76.0 13.2 62.8 30.7 12.3 43 13 30.0 36 79.3 2.3 81.6 10.9 70.7 45.5 11.3 56.8 16.3 40.5 In summary, superior CMR4 rates are achieved with high-dose imatinib adapted to good tolerability, and more patients in the tolerability-adapted 800 mg arm have stable CMR4 qualifying for treatment discontinuation as compared to the 400 mg based arms. With improved application imatinib remains first choice for early CML. Disclosures: Koschmieder: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. German CML-Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; Roche: Research Funding; BMBF: Research Funding; Essex: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.357.357
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 4
    Online Resource
    Online Resource
    Molecular Response After 3 Months of 1st Line Imatinib Therapy Is Predictive for Treatment Failure and Disease Progression In Patients with Chronic Phase Chronic Myeloid Leukemia - a Follow-up Analysis of the German CML Study IV
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 360-360
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 360-360
    Abstract: Abstract 360 Introduction: The lack of a sufficient response to first line imatinib treatment has been observed in a substantial proportion of CML patients and has been associated with an inferior survival. Therefore, response criteria have been defined to identify patients with treatment failure. A change of drug therapy to 2nd generation tyrosine kinase inhibitors or allogeneic stem cell transplantation is recommended for this group of patients (European LeukemiaNet, ELN, Baccarani et al., JCO 2009). We sought to evaluate the predictive value of early molecular response landmarks for treatment failure and disease progression to identify patients at risk and to provide a guidance for the interpretation of BCR-ABL levels. Patients and methods: 949 patients included into the randomized German CML Study IV and treated with an imatinib based therapy consisting of standard dose imatinib (400 mg/d), high dose imatinib (800 mg/d) and combinations of standard dose imatinib with low dose cytarabine or interferon alpha were evaluable for molecular and cytogenetic analysis. BCR-ABL (IS) was determined by quantitative RT-PCR. The type of BCR-ABL transcript (b2a2, n=424; b3a2, n=464; b2a2 and b3a2, n=148) was defined by multiplex PCR. Patients with atypical BCR-ABL transcripts were excluded from the analysis. Cytogenetic response (CyR) was determined by G-banding metaphase analyses. Treatment failure has been defined according to ELN criteria as a lack of major CyR after 12 months and a lack of complete CyR after 18 months of imatinib treatment, respectively. CyR data were available for 479 pts between 12 and 18 months with a subset of 289 pts evaluable for 3 month molecular response (CyR data after 18 months, n=532; 3 month molecular subset, n=289). Disease progression comprises the incidence of accelerated phase, blast phase and death. Median follow-up for disease progression was 35 months (range 2–85). Fisher's exact test has been performed to evaluate the prognostic significance of 3 month BCR-ABL landmarks for 12 month and 18 month treatment failure. A landmark analysis has been performed for disease progression (logrank test). Results: In 20 of 289 evaluable pts treatment failure has been observed after 12 months, and in 29 of 289 pts after 18 months. 24 of 570 evaluable pts showed a disease progression after a median of 18 months (range 5–71). A stratification into three groups at 3 months reveals a significant difference concerning treatment failure between pts with BCR-ABL levels between 1% and 10% and those with BCR-ABL levels 〉 10%. With regard to disease progression there is a statistical trend. Comparing two groups the 10% BCR-ABL cut-off is highly significant for both, treatment failure and disease progression. Missing the 10% BCR-ABL landmark after 3 months of imatinib treatment defines a poor risk group with a 20.7% risk of treatment failure after 18 months and a 8.1% risk of disease progression (Table). Conclusion: Early assessment of molecular response after 3 months of imatinib therapy allows the identification of a patient cohort with an increased risk of treatment failure and disease progression. Disclosure: Müller: Novartis Corporation: Honoraria, Research Funding. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Hochhaus:Novartis Corporation: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.360.360
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 5
    Online Resource
    Online Resource
    Time-Related Interpretation of Molecular Response Levels According to Long Term Overall and Progression-Free Survival of CML Patients on First-Line Imatinib Treatment
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 1681-1681
    Details
    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
    URL: Article
    DOI: 10.1182/blood.V118.21.1681.1681
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 6
    Online Resource
    Online Resource
    Distinct Characteristics of e13a2 versus e14a2 BCR-ABL Chronic Myeloid Leukemia under Upfront Treatment with Imatinib – an Analysis of the German CML Study IV,
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 3773-3773
    Details
    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
    URL: Article
    DOI: 10.1182/blood.V118.21.3773.3773
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 7
    Online Resource
    Online Resource
    Prediction of Molecular Response of Chronic Phase CML Patients by the EUTOS Score: Results of the Randomized CML-Study IV,
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 3762-3762
    Details
    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
    URL: Article
    DOI: 10.1182/blood.V118.21.3762.3762
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 8
    Online Resource
    Online Resource
    Molecular and Cytogenetic Response After 3 Months of Imatinib Treatment Is Predictive for the Risk of Disease Progression and Death in Newly Diagnosed Chronic Myeloid Leukemia Patients – a Follow-up Analysis of the German CML Study IV
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 783-783
    Details
    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
    URL: Article
    DOI: 10.1182/blood.V118.21.783.783
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 9
    Online Resource
    Online Resource
    Complete Molecular Remission (CMR 4.5) of CML Is Induced Faster by Dose – Optimized Imatinib and Predicts Better Survival - Results From the Randomized CML-Study IV
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 67-67
    Details
    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
    URL: Article
    DOI: 10.1182/blood.V120.21.67.67
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 10
    Online Resource
    Online Resource
    Secondary Malignancies in CML Patients – Data From the German CML Study IV
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 3746-3746
    Details
    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
    URL: Article
    DOI: 10.1182/blood.V120.21.3746.3746
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...